Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect

ABSTRACT

The present invention relates to a composition for preserving cells, tissues and organs, comprising as an active ingredient indole and indazole compounds of formula (1), or a pharmaceutically acceptable salt or isomer thereof, which are effective for preventing injury of organs, isolated cell systems or tissues caused by cold storage, transplant operation or post-transplantation reperfusion; a preservation method; and a preparation method of the composition.

TECHNICAL FIELD

The present invention relates to a composition for preserving cells,tissues or organs of animals comprising an indole or indazole compoundof formula (1) or a pharmaceutically acceptable salt or isomer thereofas an effective ingredient, a preservation method by using the same anda method for preparing the same. Specifically, the indole and indazolecompounds according to the present invention are effective in protectingcells, tissues and organs of animals to be transplanted and preventingtheir injury caused during transportation or storage. Furthermore, theindole and indazole compounds according to the present invention protectorgans from injury of tissues or organs caused by reperfusion aftertransplantation.

BACKGROUND ART

Recently, cases of organ transplantation have increased according to thedevelopment of surgical operation technique and medicines such asimmunosuppressant. A number of patients are in need of transplants butmany organs are not kept in a proper condition for use and thusdiscarded. Thus, it has been reported that there are still many patientsawaiting transplant surgeries. It is most preferable that an organ istransplanted to a recipient as soon as it is removed from a donor.However, many transplant surgeries are not done immediately as such.Therefore, the extended time of storage and improved quality of organsto be transplanted by improving storage method remain as urgenttechnical problems.

In these days, low temperature storage (below 20□, typically below 4□)is utilized to preserve organs, which inhibits metabolism rather thanprovides appropriate physiological conditions in vivo. A various kind ofpreserving solutions for such method have been developed and usedclinically.

At an early stage, Euro-Collin's solution was used. Recently, UWsolution (University of Wisconsin, Wahlberg, J. A., et al.,Transplantation, 43, pp. 5□8, 1987) has been developed, which is usefulas a preserving solution for liver, intestine and kidney as well aspancreas and capable of preserving liver up to 24 hours experimentally.However, in clinical tests, it is used for a shorter period to protectthe patients. Thus, preserving solutions or additional agents capable ofmaintaining viability of organs for more extended time and providingeffective storage of organs are strongly required to be developed.

Indole and indazole compounds according to the present invention have avery suitable structure to medical purpose, and a number of researcheson compounds having an indole core structure have been published. Forexample, their activities to glucokinase (WO2006/112549), usefulness asanti-cancer drug and cardiovascular angiogenesis inhibitor (WO95/07276)and as antibiotics (WO2004/018428) are representatively known.

DISCLOSURE OF THE INVENTION

The inventors of the present invention carried out intensive andextensive researches to develop compounds which can inhibit necrosis ofvarious animal cells in preserving various tissues, organs or blood andthus can provide an extended preservation period, enhanced protectioneffect and improved organ function after transplantation. As a result,we have now found out that the indole and indazole derivativesrepresented by the following formula (1) show remarkable effects asdescribed below. Indole and indazole compounds according to the presentinvention have been already disclosed and claimed in Korean PatentApplication Nos. 10-2007-0082687, 10-2008-0080519 and 10-2008-0080537,which were filed by the present applicant.

Accordingly, the present invention provides a composition for preservingcells, tissues or organs of animals comprising an indole or indazolecompound represented by formula (1) or a pharmaceutically acceptablesalt or isomer thereof as an effective ingredient, with apharmaceutically acceptable carrier.

The present invention also provides a preparation method of acomposition for preserving cells, tissues or organs of animals,specifically for preventing injury of organs, isolated cell systems ortissues caused by cold storage, transplant operation orpost-transplantation reperfusion, said method comprising a step ofmixing a compound represented by formula (1) or a pharmaceuticallyacceptable salt or isomer thereof as an effective ingredient, togetherwith a pharmaceutically acceptable carrier.

The present invention also provides a method of using the compositionaccording to the present invention comprising a compound represented byformula (1) or a pharmaceutically acceptable salt or isomer thereof asan effective ingredient, for preserving cells, tissues or organs ofanimals for transplantation.

The composition of the present invention uses an indole or indazolecompound represented by the following formula (1), or a pharmaceuticallyacceptable salt or isomer thereof as an effective ingredient:

wherein

X represents C or N,

n is 0 or 1, and n is 1 when X is C and n is 0 when X is N,

A represents a direct bond, C₃-C₈-cycloalkyl, phenyl, or 5˜6-memberedheteroaryl or heterocycle, each of which includes 1˜3 heteroatomsselected from N, O and S atoms,

R1 represents hydrogen, —C(O)—B—X′—R7 or —(CR5R6)_(m)-B—X′—R7,

m is an integer of 0 to 4,

each of R5 and R6 independently represents hydrogen or C₁-C₅-alkyl,

B represents a direct bond, C₃-C₈-cycloalkyl optionally containing oxo,or 3˜10-membered heterocycle or heteroaryl, each of which includes 1˜3heteroatoms selected from O, S and N atoms,

X′ represents a direct bond, —C(O)—, —SO₂—, —CO₂— or —C(O)NR5-,

R7 represents hydrogen, C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl, halogen,(CR5R6)_(m)-phenyl, (CR5R6)_(m)-hydroxy or (CR5R6)_(m)-heterocycle wherethe heterocycle optionally contains oxo and is a 3˜10-membered ringincluding 1˜3 heteroatoms selected from N, O and S atoms,

R2 represents —(CR5R6)_(m)-D-X″—R8,

D represents a direct bond or a 3˜10-membered heterocycle or heteroaryl,each of which optionally contains oxo and is optionally fused, andincludes 1˜4 heteroatoms selected from N, O and S atoms,

X″ represents a direct bond, —C(O)—, —C(O)O—, —NR5C(O)—, —C(O)NR5- or—O—,

R8 represents hydrogen, halogen, C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl,tri(C₁-C₆-alkyl)silane or hydroxy-C₁-C₆-alkyl,

R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or(CR5R6)_(m)-D-R9,

R9 represents hydrogen, halogen, C₁-C₆-alkyl, cyano, nitro orC₁-C₆-alkoxy,

R4 represents —(CR5R6)_(m)—Y-D-R10,

Y represents a direct bond, —C(O)O— or —O—, and

R10 represents hydrogen, nitro, halogen, C₁-C₆-alkyl,carboxy-C₁-C₆-alkyl, aryl or —C(O)O—R5,

wherein each of said alkyl, alkoxy, aryl, cycloalkyl, heterocycle andheteroaryl may be optionally substituted with one or more substituentsselected from the group consisting of hydroxy, halogen, nitrile, amino,C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, C₁-C₆-alkyl,halogeno-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkoxy and oxo.

In the definition of the substituents of the compound of the formula (1)according to the present invention, the term “alkyl” means an aliphatichydrocarbon radical. Alkyl may be a “saturated alkyl” not includingalkenyl or alkynyl moiety, or “unsaturated alkyl” including at least onealkenyl or alkynyl moiety. “Alkenyl” means a group having at least onecarbon-carbon double bond and “alkynyl” means a group having at leastone carbon-carbon triple bond. Alkyl may be a branched or straight chainwhen used alone or in combination with alkoxy.

Alkyl may have 1˜20 carbon atoms unless defined otherwise herein. Alkylmay be a medium-sized alkyl having 1˜10 carbon atoms. Alkyl may be alower alkyl having 1˜6 carbon atoms. Typical alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, etc. For example,C₁-C₄-alkyl has 1˜4 carbon atoms in alkyl chain and is selected from thegroup consisting of methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl and tert-butyl.

The term “alkoxy” means alkyloxy having 1˜10 carbon atoms unless definedotherwise herein.

The term “cycloalkyl” means saturated aliphatic 3˜10-membered cycleunless defined otherwise herein. Typical cycloalkyl groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,etc.

“Aryl” includes at least one ring having shared pi electron system, forexample, monocyclic or fused-polycyclic groups (i.e., rings sharingadjacent carbon pairs). In other word, the term “aryl” used herein means4˜10-membered, preferably 6˜10-membered aromatic monocyclic ormulticyclic ring and includes, for example, phenyl and naphtyl.

The term “heteroaryl” means 3˜10-membered, preferably 4˜8-membered, morepreferably 5˜6-membered aromatic ring, which includes 1˜3 heteroatomsselected from N, O and S atoms and may be fused with benzo or C₃-C₈cycloalkyl, unless defined otherwise herein. Examples of monocyclicheteroaryl include, but are not limited to, thiazole, oxazole,thiophene, furan, pyrole, imidazole, isoxazole, isothiazole, pyrazole,triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine,pyridazine, pyrimidine, pyrazine and analogs thereof. Examples ofbicyclic heteroaryl include, but are not limited to, indole, indoline,benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline,purine, furopyridine and analogs thereof.

The term “heterocycle” means 3˜10 membered, preferably 4˜8-membered, andmore preferably 5˜6-membered ring which includes 1˜3 heteroatomsselected from N, O and S atoms and may be fused with benzo orC₃-C₈-cycloalkylalkyl, and may be saturated or contain 1 or 2 doublebonds. Examples of heterocycle includes, but are not limited to,pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline,pyrazolidine, pyrane, piperidine, morpholine, thiomorpholine,piperazine, hydrofuran, etc.

The other terms and abbreviations used herein can be understood by aperson skilled in the art as having conventional definitions unlessdefined otherwise herein.

Preferable compounds among the compounds of formula I according to thepresent invention are those wherein

X represents C or N,

n is 0 or 1, and n is 1 when X is C and n is 0 when X is N,

A represents a direct bond, phenyl, or 5˜6-membered heteroaryl orheterocycle, each of which includes 1˜3 heteroatoms selected from N, Oand S atoms,

R1 represents hydrogen, —C(O)—B—X′—R7 or —(CR5R6)_(m)-B—X′—R7,

m is an integer of 0 to 2,

each of R5 and R6 independently represents hydrogen or C₁-C₅-alkyl,

B represents a direct bond, C₄-C₇-cycloalkyl optionally containing oxoand optionally substituted with halogen, or 4˜8-membered heterocycle orheteroaryl, each of which includes 1˜3 heteroatoms selected from O, Sand N atoms,

X′ represents a direct bond, —C(O)—, —SO₂—, —CO₂— or —C(O)NH—,

R7 represents hydrogen, C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl, halogen,(CR5R6)_(m)-phenyl, (CR5R6)_(m)-hydroxy or (CR5R6)_(m)-heterocycle wherethe heterocycle optionally contains oxo and is a 4˜8-membered ringincluding 1˜3 heteroatoms selected from N, O and S atoms,

R2 represents —(CR5R6)_(m)-D-X″—R8,

D represents a direct bond or a 4˜8-membered heterocycle or heteroaryl,each of which optionally contains oxo and is optionally fused, andincludes 1˜4 heteroatoms selected from N, O and S atoms,

X″ represents —C(O)—, —C(O)O—, —NR5C(O)—, —C(O)NR5- or —O—,

R8 represents hydrogen, halogen, C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl,tri(C₁-C₆-alkyl)silane or hydroxy-C₁-C₆-alkyl,

R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or(CR5R6)_(m)-D-R9,

R9 represents hydrogen, halogen, C₁-C₆-alkyl, cyano, nitro orC₁-C₆-alkoxy,

R4 represents —(CR5R6)_(m)—Y-D-R10,

Y represents a direct bond, —C(O)O— or —O—, and

R10 represents hydrogen, nitro, halogen, C₁-C₆-alkyl,carboxy-C₁-C₆-alkyl, aryl or —C(O)O—R5.

In the compound of formula (1) according to the present invention, X isC or N and the compound structure for each case may be represented bythe following formula (1a) or (1b), respectively.

In the compound of formula (1) according to the present invention, thesubstituent A is more preferably selected from the group consisting ofphenyl, pyridine, 1,4-pyrazine, 4,5-dihydro-thiazole, thiazole,4,5-dihydrooxazole, [1,2,4]oxadiazole and [1,3,4]oxadiazole.

More preferably, the substituent R1 represents —C(O)—B—X′—R7 or—(CHR5)_(m)-B—X′—R7 where m is an integer of 0 to 2; R5 representsC₁-C₃-alkyl; B represents a direct bond, C₅-C₆-cycloalkyl optionallycontaining oxo, or 5˜6-membered heterocycle or heteroaryl, each of whichincludes 1˜3 heteroatoms selected from O, S and N atoms; X′ represents adirect bond, —C(O)—, —SO₂—, —CO₂— or —C(O)NH—; and R7 representshydrogen, C₁-C₃-alkyl, halogeno-C₁-C₃-alkyl, halogen, (CH₂)_(m)-phenyl,(CH₂)_(m)-hydroxy or (CH₂)_(m)-heterocycle where the heterocycleoptionally contains oxo and is a 5˜6-membered ring including 1˜3heteroatoms selected from N, O and S atoms. In the substituent R1, B ismost preferably selected from the group consisting of cyclopentyl,cyclohexyl, piperidine, tetrahydropyran, oxocyclohexyl, pyrrolidine,difluorocyclohexyl and tetrahydrofuran; and R7 is most preferablyselected from the group consisting of hydrogen, methyl, ethyl,isopropyl, benzyl, hydroxymethyl, (morpholine-4-yl)-ethyl,tetrahydrofuran, 2,2,2-trifluoroethyl, hydroxyethyl,1,1-dioxothiomorpholine, tetrahydropyran, (tetrahydropyran-4-yl)-methyland trifluoromethyl.

In the substituent R2, more preferably, D represents a direct bond, oris selected from the group consisting of piperazine, pyrrolidine,morpholine, 1,1-dioxothiomorpholine and oxopiperazine; and R8 is morepreferably selected from the group consisting of hydrogen, ethyl,hydroxymethyl, methyl and fluorine.

More preferably, the substituent R3 represents hydrogen; halogen; phenyloptionally substituted with alkoxy; or 6-membered heterocyclylmethylincluding 1˜3 heteroatoms selected from N, S and O atoms as ring membersand optionally containing oxo. R3 is most preferably selected from thegroup consisting of hydrogen, bromine, phenyl, methoxy-phenyl,morpholine-4-yl-methyl, oxopiperazine-4-yl-methyl and1,1-dioxo-thiomorpholine-4-yl-methyl.

More preferably, the substituent R4 represents —(CH₂)_(m)—Y-D-R10 wherem is an integer of 0 to 2; Y represents a direct bond, —C(O)O— or —O—; Drepresents pyridine or 5˜6-membered heterocycle including 1˜3heteroatoms selected from N, S and O atoms and optionally containingoxo; and R10 represents hydrogen, halogen, C₁-C₃-alkyl, —(CH₂)—CO₂H,aryl or —C(O)O—R5 where R5 represents hydrogen or C₁-C₃-alkyl. In thesubstituent R4, D is most preferably selected from the group consistingof 1,1-dioxo-thio-morpholine, oxopiperazine, pyridine, morpholine and4,5-dihydro-thiazole; and R10 is most preferably selected from the groupconsisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl and—(CH₂)—CO₂H.

The representative compounds of formula (1) according to the presentinvention include the following compounds:

-   cyclopentyl-[2-(4,5-dihydro-1,3-thiazole-2-yl)-1H-indole-7-yl]-amine;-   [2-(4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-(4-methyl-cyclohexyl)-amine;-   [2-(4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-piperidine-4-yl-amine;-   2-5-[7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-[1,2,4]oxadiazole-3-yl}-ethanol;-   [(R)-2-(7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-1,3-thiazole-4-yl]-methanol;-   cyclopentyl-[2-((R)-4-pyrrolidine-1-ylmethyl-4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-amine;-   {(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-met    hanol;-   [(R)-2-(7-cyclopentylamino-5-fluoro-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-methan    ol;-   {(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-methanol;-   {(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihyd    ro-thiazole-4-yl}-methanol;-   [(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic    acid;-   [(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic    acid ethyl ester;-   2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazol    e-4-yl}-ethanol;-   1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-th    iazole-4-yl}-ethyl)-piperazine-1-yl]-2-hydroxy-ethanone;-   1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiaz    ole-4-yl}-ethyl)-pyrrolidine-3-ol;-   [(R)-2-(5-bromo-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic    acid;-   [2-(7-cyclopentylamino-5-phenoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceti    c acid;-   [(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceti    c acid;-   3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-propi    onic acid ethyl ester;-   3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-propi    onic acid;-   cyclopentyl-(2-pyridine-2-yl-1H-indole-7-yl)-amine;-   cyclopentyl-(2-pyrazine-2-yl-1H-indole-7-yl)amine;-   (2-pyrazine-2-yl-1H-indole-7-yl)-(tetrahydropyran-4-yl)-amine;-   cyclopentyl-(2-thiazole-2-yl-1H-indole-7-yl)-amine;-   2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-4-carboxylic    acid ethyl ester;-   2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-4-carboxylic    acid;-   [2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-4-yl]-methanol;-   [2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-5-yl]-methanol;-   cyclopentyl-(5-methyl-2-[1,3,4]oxadiazole-2-yl-1H-indole-7-yl)-amine;-   cyclopentyl-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;-   (5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-(tetrahydro-pyran-4-yl)-amine;-   cyclohexyl-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;-   1-[4-(5-methyl-2-pyridine-2-yl-1H-indole-7-ylamino)-piperidine-1-yl]-ethanone;-   (1-methyl-piperidine-4-yl)-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;-   4-(5-methyl-2-pyridine-2-yl-1H-indole-7-ylamino)-cyclohexanone;-   (1-benzyl-pyrrolidine-3-yl)-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;-   cyclopentylmethyl-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;-   N-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-benzamide;-   cyclopentyl-(5-methyl-2-pyrazine-2-yl-1H-indole-7-yl)-amine;-   cyclopentyl-(5-ethoxy-2-pyridine-2-yl-1H-indole-7-yl)-amine;-   cyclopentyl-(5-phenoxy-2-pyridine-2-yl-1H-indole-7-yl)-amine;-   cyclopentyl-(3,5-dimethyl-2-phenyl-1H-indole-7-yl)-amine;-   cyclopentyl-(5-methyl-2-phenyl-1H-indole-7-yl)-amine;-   (2-cyclohexyl-5-methyl-1H-indole-7-yl)-cyclopentyl-amine;-   cyclopentyl-[5-methyl-2-(6-methyl-pyridine-2-yl)-1H-indole-7-yl]-amine;-   (5-methyl-2-phenyl-1H-indole-7-yl)-(tetrahydro-pyran-4-yl)-amine;-   (5-methyl-2-phenyl-1H-indole-7-yl)-(1-methyl-piperidine-4-yl)-amine;-   1-[4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-piperidine-1-yl]-ethanone;-   (5-methyl-2-phenyl-1H-indole-7-yl)-piperidine-4-yl-amine    hydrochloride;-   2-hydroxy-1-[4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-piperidine-1-yl]-ethanone;-   (1-methanesulfonyl-piperidine-4-yl)-(5-methyl-2-phenyl-1H-indole-7-yl)-amine;-   4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-cyclohexanecarboxylic    acid;-   4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-cyclohexanecarboxylic acid    (2-morpholine-4-yl-ethyl)-amide;-   cyclopentylmethyl-(5-methyl-2-phenyl-1H-indole-7-yl)-amine;-   (5-methyl-2-phenyl-1H-indole-7-yl)-(tetrahydro-pyran-4-ylmethyl)-amine;-   (5-chloro-2-phenyl-1H-indole-7-yl)-cyclopentyl-amine;-   (5-chloro-2-phenyl-1H-indole-7-yl)-(tetrahydro-pyran-4-yl)-amine;-   (5-chloro-2-phenyl-1H-indole-7-yl)-(1-methyl-piperidine-4-yl)-amine;-   (5-chloro-2-phenyl-1H-indole-7-yl)-cyclohexyl-amine;-   (1-benzyl-pyrrolidine-3-yl)-(5-chloro-2-phenyl-1H-indole-7-yl)-amine;-   4-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoic acid methyl    ester;-   4-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoic acid;-   [4-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-phenyl]-methanol;-   4-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-benzoic acid methyl    ester;-   2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoic acid methyl    ester;-   2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoic acid;-   [2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-phenyl]-methanol;-   7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester;-   7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid;-   (7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-methanol;-   (7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-acetic acid ethyl    ester;-   (7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-acetic acid;-   2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazol    e-4-yl]acetic acid;-   2-[(4S)-2-[5-chloro-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazol    e-4-yl]acetic acid;-   2-[(4S)-2-[7-[(4,4-difluorocyclohexyl)amino]-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic    acid;-   2-[(4S)-2-[7-(oxane-4-ylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-y    l]acetic acid;-   2-[(4R)-2-[7-(oxane-4-ylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-y    l]acetic acid;-   2-[(4R)-2-[7-(oxane-4-ylmethylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thiaz    ole-4-yl]acetic acid;-   2-[(4S)-2-[7-(cyclopentylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic    acid;-   2-[(4S)-2-[7-[(1-acetylpyrrolidine-3-yl)amino]-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic    acid;-   2-[(4S)-2-[7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ace    tic acid;-   2-[(4S)-2-[7-(oxane-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic    acid;-   2-[(4S)-2-[7-(oxane-2-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ace    tic acid;-   2-[(4S)-2-[5-methyl-7-[[1-(3,3,3-trifluoropropanoyl)piperidine-4-yl]amino]-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic    acid;-   2-[(4R)-2-[7-(cyclopentylamino)-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic    acid;-   2-[(4R)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazol    e-4-yl]acetic acid;-   4-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thia    zole-4-yl]ethyl]piperazine-2-one;-   2-[(4S)-4-[2-(1,1-dioxo-1,4-thiazinane-4-yl)ethyl]-4,5-dihydro-1,3-thiazole-2-yl]-5-meth    yl-N-(oxane-4-ylmethyl)-1H-indole-7-yl-amine;-   N-(4,4-difluorocyclohexyl)-5-methyl-2-[(4S)-4-(2-morpholine-4-ylethyl)-4,5-dihydro-1,3-thiazole-2-yl]-1H-indole-7-yl-amine;-   4-[2-[(4S)-2-[7-[(4,4-difluorocyclohexyl)amino]-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]piperazine-2-one;-   4-[2-[(4S)-2-[7-(oxane-4-ylmethylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thi    azole-4-yl]ethyl]piperazine-2-one;-   2-[(4    S)-4-(2-morpholine-4-ylethyl)-4,5-dihydro-1,3-thiazole-2-yl]-N-(oxane-4-ylmethyl)-5-phenoxy-1H-indole-7-amine;-   5-methyl-2-[(4    S)-4-(2-morpholine-4-ylethyl)-4,5-dihydro-1,3-thiazole-2-yl]-N-(oxane-4-ylmethyl)-1H-indole-7-amine;-   1-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thia    zole-4-yl]ethyl]piperidine-4-carboxyamide;-   [(2R)-1-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]pyrrolidine-2-yl]methanol;-   (2S)-1-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]pyrrolidine-2-carboxyamide;-   4-[2-[(4R)-2-[7-(cyclopentylamino)-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]piperazine-2-one;-   2-[(4S)-2-[7-(cyclopentylamino)-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-oxazole-4-yl    ]acetic acid;-   {(S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-oxazole-4-yl}-acetic    acid;-   2-[(4S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-oxa    zole-4-yl]ethanol;-   {5-methyl-2-[(S)-4-(2-morpholine-4-yl-ethyl)-4,5-dihydro-1,3-oxazole-2-yl]-1H-indole-7-yl}-(tetrahydro-pyran-4-yl)amine;-   4-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]-N-ethylpiperidine-1-carboxyamide;-   [4-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]piperidine-1-yl]-(oxolan-3-yl)methanone;-   2-[7-(oxane-4-ylamino)-2-phenyl-1H-indole-5-yl]acetic acid;-   2-[7-(cyclopentylmethylamino)-2-phenyl-1H-indole-5-yl]acetic acid;-   5-fluoro-N-(1-methylpiperidine-4-yl)-2-phenyl-1H-indole-7-amine;-   2-[4-[(5-fluoro-2-phenyl-1H-indole-7-yl)amino]piperidine-1-yl]ethanone;-   5-fluoro-N-[1-(oxane-4-yl)piperidine-4-yl]-2-phenyl-1H-indole-7-amine;-   N-[1-(1,1-dioxan-4-yl)piperidine-4-yl]-5-fluoro-2-phenyl-1H-indole-7-amine;-   N-(oxane-4-yl)-5-phenoxy-2-phenyl-1H-indole-7-amine;-   methyl 2-[(5-fluoro-2-phenyl-1H-indole-7-yl)amino]acetate;-   2-[(5-fluoro-2-phenyl-1H-indole-7-yl)amino]acetic acid;-   methyl 2-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]propanoate;-   2-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]propanoic acid;-   2-[(5-phenoxy-2-phenyl-1H-indole-7-yl)amino]acetic acid;-   2-[(5-phenoxy-2-phenyl-1H-indole-7-yl)amino]propanoic acid;-   2-[(4S)-2-[7-(oxane-4-ylmethylamino)-2-phenyl-1H-indole-5-yl]-4,5-dihydro-1,3-thiazol    e-4-yl]acetic acid;-   2-[(4S)-2-[7-(cyclopentylamino)-2-phenyl-1H-indole-5-yl]-4,5-dihydro-1,3-thiazole-4-yl    ]acetic acid;-   methyl    2-[4-[5-chloro-7-(oxane-4-ylamino)-1H-indole-2-yl]phenyl]acetate;-   methyl    2-[4-[5-chloro-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]phenyl]acetate;-   2-[4-[5-chloro-7-(oxane-4-ylamino)-1H-indole-2-yl]phenyl]acetic    acid;-   5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;-   5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-ylmethyl)-2-phenyl-1H-indole-7-a    mine;-   4-[[7-(oxane-4-ylamino)-2-phenyl-1H-indole-5-yl]methyl]piperazine-2-one;-   5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-phenyl-N-piperidine-4-yl-1H-indole-7-amin    e;-   [4-[[5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-phenyl-1H-indole-7-yl]amino]piperidin    e-1-yl]-(oxolan-3-yl)methanone;-   N-[4-[5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-7-(oxane-4-ylamino)-1H-indole-2-yl]ph    enyl]acetamide;-   N-[4-[7-(dicyclopentylamino)-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-1H-indole-2-yl]    phenyl]acetamide;-   N-[4-[5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]phenyl]acetamide;-   N-cyclopentyl-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(4-methoxyphenyl)-1H-indol    e-7-amine;-   5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(4-methoxyphenyl)-N-(oxane-4-yl)-1H-indo    le-7-amine;-   5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(3-methoxybutyl)-2-phenyl-1H-indole-7-am    ine;-   5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(3-fluorophenyl)-N-(oxane-4-yl)-1H-indole-7-amine;-   N-cyclopentyl-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(3-fluorophenyl)-1H-indole-7-amine;-   3-bromo-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;-   3-bromo-5-(morpholine-4-ylmethyl)-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;-   3-bromo-N-cyclopentyl-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-phenyl-1H-indole-7-amine;-   3-bromo-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;-   5-chloro-N-(oxane-4-yl)-3-phenyl-1H-indole-7-amine;-   5-chloro-N-cyclopentyl-3-phenyl-1H-indole-7-amine;-   5-chloro-N-(oxane-4-ylmethyl)-3-phenyl-1H-indole-7-amine;-   5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-3-phenyl-2-trimethylsilyl-1H-i    ndole-7-amine;-   4-[[5-chloro-7-(cyclopentylamino)-2-phenyl-1H-indole-3-yl]methyl]piperazine-2-one;-   4-[[5-chloro-7-(oxane-4-ylamino)-2-phenyl-1H-indole-3-yl]methyl]piperazine-2-one;-   4-[[5-chloro-7-(oxane-4-ylmethylamino)-2-phenyl-1H-indole-3-yl]methyl]piperazine-2-o    ne;-   N-cyclopentyl-3-(4-methoxyphenyl)-1H-indazol-7-amine;-   3-(4-methoxyphenyl)-N-(oxane-4-yl)-1H-indazol-7-amine;-   3-(4-methoxyphenyl)-N-(oxane-4-ylmethyl)-1H-indazol-7-amine; and-   2-(7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-ethanol.

In addition, the terms and abbreviations used herein have their originalmeanings unless defined otherwise.

The compound of formula (1) according to the present invention may alsoform pharmaceutically acceptable salts. Such pharmaceutically acceptablesalts include acid-addition salts formed by acid to form a non-toxicacid addition salt having pharmaceutically acceptable anion including,for example, inorganic acid such as hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and thelike; organic acid such as tartaric acid, formic acid, citric acid,acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid,benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid andthe like; sulfonic acid such as methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Inaddition, for example, pharmaceutically acceptable carboxylic acid saltsinclude alkali metal salts or alkali earth metal salts formed bylithium, sodium, potassium, calcium, magnesium and the like; amino acidsalts of lysine, arginine, guanidine and the like; organic salts such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,diethanolamine, choline, triethylamine and the like. The compound offormula (1) according to the present invention may be converted to itssalt by conventional methods.

Meanwhile, the compound according to the present invention can haveasymmetric carbon center(s), and so can be present as R or S isomericforms, racemates, diastereomeric mixtures, and individual diastereomers.The present invention encompasses all of these isomeric forms andmixtures.

The present invention also provides a process for preparing the compoundof formula (1). Hereinafter, to help understanding the presentinvention, the processes for the preparation of the compound of formula(1) are explained based on exemplary reaction schemes. However, itshould be construed that a person skilled in the art could prepare thecompound of formula (1) according to various methods based on thestructure of formula (1), and such methods are included in the scope ofthe present invention. That is, the compound of formula (1) can beprepared by optionally combining various methods described in thepresent specification and/or disclosed in prior arts, which are includedin the range of the present invention, and so the processes for thepreparation of compound of formula (1) are not limited to thoseexplained below.

The compound of formula (1) may be prepared according to the followingReaction Scheme (1) by reducing nitro group of compound (2) to obtainamine compound (3) and then introducing a substituent to the formedamine group. Alternatively, the compound of formula (1) may be preparedaccording to the following Reaction Schemes (2) to (8) by modifying thesubstituents R3, R5, R6, R7 of compound (4).

In the above Reaction Scheme 1,

a is Fe, Zn, or H₂ (Pd/C);

b is an acylation agent in the form of R7-B—CO—W, wherein R7 and B arethe same as defined in formula (1), W is OH or a leaving group such aschloride, bromide, iodide, mixed anhydride and the like;

c is ketone in the form of R7-B═O or aldehyde compound in the form ofR7-B—CHO, sodium triacetoxyborohydride (NaBH(OAc)₃) or sodiumcyanoborohydride (NaBH₃CN);

R3 is the same as defined in Formula (1);

R11 represents A-R2 or CO₂R12, wherein A and R2 are the same as definedin formula (1), R12 represents C₁-C₆-alkyl;

R4 is the same as defined in formula (1); and

R1 is the same as defined in formula (1).

Compound (2) may be prepared by the methods described in the followingReaction Schemes (2) to (8).

Compound (3) may be prepared by reducing Compound (2). The reductionreaction may be carried out by using an acid catalyst and metal, or ametal catalyst in the presence of hydrogen gas.

In the reduction reaction using an acid catalyst and metal, the acidthat can be used is, for example, inorganic acid such as hydrochloricacid, sulfuric acid, nitric acid, phosphoric acid and the like;organo-carbonic acid such as acetic acid, trifluoroacetic acid and thelike; or amine acid salt such as ammonium chloride, and preferablyhydrochloric acid, acetic acid or ammonium chloride. The use amount ofacid is conventionally 0.01-10 equivalents, preferably 0.1-5 equivalentsto 1 equivalent of Compound (2). The metal that can be used is, forexample, iron, zinc, lithium, sodium, tin (conventionally, tin chloride)and the like, and preferably iron, zinc or tin chloride. The use amountof metal is conventionally 1-20 equivalents, preferably 1-10 equivalentsto 1 equivalent of Compound (2). The reaction of metal in the presenceof acid catalyst may be carried out in an inert solvent. Such inertsolvent is, for example, alkyl alcohol such as methanol, ethanol and thelike; ether such as tetrahydrofuran, diethyl ether and the like; oralkyl ester such as ethyl acetate, and preferably methanol, ethanol,tetrahydrofuran or ethyl acetate. The reaction temperature isconventionally −10 to 200□, preferably 25 to 120□, and the reaction timeis conventionally 10 minutes—60 hours, and preferably 10 minutes—12hours.

In the reduction reaction in the presence of hydrogen gas, the metalcatalyst that can be used is palladium, nickel, platinum, ruthenium,rhodium and the like, and preferably palladium, nickel or the like. Theuse amount of metal catalyst is conventionally 0.001-2 equivalents, andpreferably 0.01-1 equivalent to 1 equivalent of Compound (2). Thepressure of hydrogen gas is conventionally 1-10 atms, and preferably 1-3atms. The reaction may be carried out in an inert solvent, for example,alkyl alcohol such as methanol, ethanol and the like; ether such astetrahydrofuran, diethyl ether and the like; or alkyl acetate such asmethyl acetate, ethyl acetate and the like, and preferably methanol,ethanol or ethyl acetate. The temperature of reaction using metalcatalyst is conventionally −10 to 200□, and preferably 25 to 50□, andthe reaction time is conventionally 10 minutes-60 hours, and preferably10 minutes-12 hours.

Compound (4) may be prepared though acylation reaction or reductivealkylation reaction of Compound (3).

The acylation reaction to amine group of Compound (3) may be carried outby using an acylation agent in the presence of a base. The base that canbe used is an organic base such as triethylamine, diisopropylethylamine,pyridine, N-methylmorpholine and the like. The use amount of base isconventionally 1-10 equivalents, and preferably 1-5 equivalents to 1equivalent of Compound (3). The use amount of acylation agent isconventionally 1-10 equivalents, and preferably 1-3 equivalents to 1equivalent of Compound (3). The reaction may be carried out in an inertsolvent, for example, ether such as tetrahydrofuran, diethyl ether andthe like; or chloroalkane such as dichloromethane, chloroform and thelike, and preferably dichloromethane or chloroform. The temperature ofreaction is conventionally −10 to 100□, preferably −10 to 50□, andreaction time is conventionally 10 minutes-60 hours, preferably 10minutes-12 hours.

The reductive alkylation to amine group of Compound (3) may be carriedout thorough the reaction with aldehyde or ketone with the use of areducing agent. An acid catalyst may also be used if necessary. Theamount of aldehyde or ketone is conventionally 1-10 equivalents, andpreferably 1-3 equivalents to 1 equivalent of Compound (3). The reducingagent that can be used is sodium borohydride, sodium cyanoborohydride,sodium triacetoxyborohydride and the like. The use amount of reducingagent is conventionally 1-10 equivalents, and preferably 1-3 equivalentsto 1 equivalent of Compound (3). The acid catalyst that can be used is,for example, inorganic acid such as hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid and the like; organo-carbonic acid such asacetic acid, trifluoroacetic acid and the like; or amine acid salt suchas ammonium chloride, and preferably hydrochloric acid or acetic acid.The use amount of acid is conventionally 0.1-10 equivalents, andpreferably 1-5 equivalents to 1 equivalent of Compound (3). The reactionmay be carried out in an inert solvent, for example, ether such astetrahydrofuran, diethyl ether and the like; or chloroalkane such asdichloromethane, chloroform, dichloroethane and the like, and preferablydichloroethane or chloroform. The temperature of reaction isconventionally −10 to 100□, preferably −10 to 50□, and the reaction timeis conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.

Compound (2) according to the present invention may be prepared by themethods concretely exemplified in the following Reaction Schemes (2) to(8).

c is PCl₅ or Tf₂O and Ph₃PO;

d is a metal catalyst (e.g., Pd/C, MnO₂, etc.) or BrCCl₃ or the like;

e is a reducing agent (e.g., NaBH₄, LiAlH₄);

f is I₂ or MsCl;

g is Compound (13);

R2 is the same as defined in formula (1);

R4 is the same as defined in formula (1);

R12 represents C₁-C₆-alkyl;

R13 represents NO₂ or R1;

R14 represents p-MeOBn or Ph₃C;

when Q is nitrogen, each of R15 and R16 independently represents H,C₁-C₆-alkyl, 6 to 12-membered aryl or 5 to 12-membered heteroaryl; orR15 and R16 may be linked with each other to form 3 to 10-membered ring;

when Q is oxygen or sulfur, R15 represents H, C₁-C₆-alkyl, 6 to12-membered aryl or 5 to 12-membered heteroaryl, and R16 is not present;and

W is a leaving group, for example, halogen such as chloride, bromide,iodide and the like, or sulfonyl such as methanesulfonyl,p-toluenesulfonyl and the like.

Compound (5) may be prepared by the method described in Reaction Scheme(7) or (8).

Compound (6) may be prepared by hydrolysis reaction of Compound (5) byusing a base. The base that can be used is lithium hydroxide, sodiumhydroxide, potassium hydroxide, metal bicarbonate, metal carbonate andthe like. The use amount of base is conventionally 1-10 equivalents,preferably 1-5 equivalents to 1 equivalent of Compound (5). Thehydrolysis reaction may be carried out in an inert solvent, for example,alkyl alcohol such as methanol, ethanol and the like; ether such astetrahydrofuran, diethyl ether and the like. The temperature of reactionis conventionally −10 to 200□, preferably 25 to 120□, and reaction timeis conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.

Compound (7) may be prepared by the method described in the followingReaction Scheme (9).

Compound (8) may be prepared by a coupling reaction of carboxylic acidgroup of Compound (6) and amine group of Compound (7). Known couplingagents that can be used in the coupling reaction include, but notlimited thereto, carboimide such as dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or1,1′-dicarbonyldiimidazole (CDI) in a mixed form with1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT),or bis-(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl),diphenylphosphoryl azide (DPPA) or N-[dimethylamino-1H-1,2,3-triazole[4,5-b]-pyridin-1-ylmethylene]-N-methylmethaneaminium (HATU). The useamount of coupling agent is conventionally 1-10 equivalents, preferably1-3 equivalents to 1 equivalent of Compound (6). The use amount of HOBTor HOAT is conventionally 1-10 equivalents, preferably 1-3 equivalentsto 1 equivalent of Compound (5). When hydrochloric acid salt of amine isused in the coupling reaction, acid should be removed with a base. Thebase that can be used for this is an organic base such as triethylamine,diisopropylethylamine and the like. The use amount of base isconventionally 1-10 equivalents, preferably 1-3 equivalents to 1equivalent of Compound (7). The coupling reaction may be carried out inan inert solvent such as tetrahydrofuran, diethylether,N,N-dimethylformamide, and the like. The temperature of reaction isconventionally −10 to 200□, preferably 25 to 120□, and reaction time isconventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.

Compound (9) may be prepared by a cyclization reaction of Compound (8)according to literatures (Journal of Organic Chemistry, 68(24), 2003,9506-9509; Tetrahedron, 55(34), 1999, 10271-10282, etc.).

When R14 is p-methoxybenzyl (p-MeOBn) group, the cyclization reaction iscarried out by using phosphorus pentachloride (PCl₅) in dichloromethanesolvent. The use amount of PCl₅ is conventionally 1-10 equivalents,preferably 1-3 equivalents to 1 equivalent of Compound (8). Thetemperature of reaction is conventionally −10 to 50□, preferably 0 to25□, and reaction time is conventionally 10 minutes-60 hours, preferably10 minutes-12 hours.

When R14 is triphenylmethyl (Ph₃C) group, the cyclization reaction iscarried out by using trifluoromethanesulfonic anhydride (Tf₂O) andtriphenyl phosphinoxide (Ph₃PO) in dichloromethane solvent. The useamount of each of them is conventionally 1-10 equivalents, preferably1-3 equivalents to 1 equivalent of Compound (8). The temperature ofreaction is conventionally −10 to 50□, preferably 0-25□, and reactiontime is conventionally 10 minutes-60 hours, preferably 10 minutes-12hours.

Compound (10) may be prepared by using a dehydrogenation agent or ametal catalyst to Compound (9), or by an introduction of a leaving grouptherein and its subsequent removal by using a base.

The dehydrogenation agent may be sulfur, selenium, various quinones{e.g., 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ)} and the like, andthe dehydrogenation metal catalyst may be palladium (conventionally,Pd/C), platinum, nickel (conventionally, NiO₂), manganese(conventionally, MnO₂) and the like. The use amount of dehydrogenationagent is conventionally 1-20 equivalents, preferably 1-5 equivalents to1 equivalent of Compound (9). The use amount of dehydrogenation metalcatalyst is conventionally 0.001-10 equivalents, preferably 0.1-1equivalent to 1 equivalent of Compound (9). A solvent that can be usedis benzene, toluene, decalin, quinoline and the like. The temperature ofreaction is conventionally 25 to 400□, preferably 25 to 200□, andreaction time is conventionally 10 minutes-60 hours, preferably 10minutes-12 hours.

A reagent that can be used in the introduction of leaving group includescooper (II) bromide (CuBr₂), bromotrichloromethane (BrCCl₃),N-bromosuccinimide (NBS) and the like. The use amount is conventionally1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound(9). The base that can be used is, for example, inorganic base such assodium carbonate, sodium bicarbonate, potassium carbonate and the like;organic base such as triethylamine, pyridine,1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) and the like; preferablysodium carbonate or DBU. The use amount of base is conventionally 0-10equivalents, preferably 0-3 equivalents to 1 equivalent of Compound (9).The solvent that can be used is an inert solvent, for example, ethersuch as tetrahydrofuran, diethyl ether and the like; chloroalkane suchas dichloromethane, dichloroethane, chloroform and the like, andpreferably dichloromethane or chloroform. The temperature of reaction isconventionally −10 to 200□, preferably 0 to 100□, and the reaction timeis conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.

Compound (11) may be prepared through the hydrolysis reaction, reductionreaction, coupling reaction of amine and acid and substitution reactionof amine, etc. of Compound (10) by using the synthesis method ofCompounds (6), (15) and (16).

Compound (12) may be prepared through the hydrolysis reaction ofCompound (9) by using the synthesis method of Compound (6).

Compound (14) may be prepared through the coupling reaction ofcarboxylic acid of Compound (12) and Compound (13) by using thesynthesis method of Compound (8).

Compound (15) may be prepared by modifying ester group of Compound (9)to alcohol group and introducing leaving group X.

A reducing agent to be used for reducing ester group to alcohol groupis, for example, sodium borohydride, lithium borohydride, borane,lithium aluminum hydride, diisobutylaluminium hydride (DIBAL-H) and thelike. The use amount of reducing agent is conventionally 1-10equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (9).The reaction may be carried out in an inert solvent, for example,alcohol such as methanol, ethanol and the like; ether such astetrahydrofuran, diethyl ether and the like; and preferablytetrahydrofuran or ether. The reaction temperature is conventionally −78to 1000, preferably −10 to 50□, and the reaction time is conventionally10 minutes-60 hours, preferably 10 minutes-12 hours.

The method to introduce a leaving group to alcohol group is ahalogenation or sulfonylation reaction. The halogenation reaction may becarried out by using a reagent such as iodine, bromine,N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), carbon tetrachloride(CCl₄), carbon tetrabromide (CBr₄) and the like in the presence of abase such as imidazole, dimethylaminopyridine (DMAP), etc. and phosphinesuch as triphenylphosphine (Ph₃P), tributylphosphine (Bu₃P), etc. Theuse amount of each of the halogenation agent, base and phosphinecompound is conventionally 1-10 equivalents, preferably 1-3 equivalentsto 1 equivalent of Compound (9). The reaction may be carried out in aninert solvent, for example, ether such as tetrahydrofuran, diethyl etherand the like; dichloromethane; chloroform; acetonitrile and the like.The temperature of reaction is conventionally −10 to 200□, preferably 0to 50□, and the reaction time is conventionally 10 minutes-60 hours,preferably 10 minutes-12 hours.

The sulfonylation reaction may be carried out by using a reagent such asmethanesulfonyl chloride, p-toluenesulfonyl chloride and the like in thepresence of an organic base such as pyridine, triethylamine and thelike. The use amount of each of the sulfonylation agent and base isconventionally 1-10 equivalents, preferably 1-5 equivalents to 1equivalent of Compound (9). The reaction may be carried out in an inertsolvent, for example, ether such as tetrahydrofuran, diethyl ether andthe like; chloroalkane such as dichloromethane, dichloroethane,chloroform and the like, and preferably dichloromethane ordichloroethane. The temperature of reaction using metal catalyst isconventionally −10 to 200□, preferably 0 to 50□, and the reaction timeis conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.

Compound (16) may be prepared by the coupling reaction of Compound (13)and Compound (15) by using a base. The base that can be used is, forexample, inorganic base such as sodium carbonate, potassium carbonate,cesium carbonate and the like; organic base such as triethylamine,diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) and thelike, and preferably potassium carbonate, cesium carbonate or DBU. Theuse amount of base is conventionally 1-10 equivalents, preferably 1-5equivalents to 1 equivalent of Compound (13). The solvent that can beused is an inert solvent, for example, ether such as tetrahydrofuran,diethyl ether and the like; alkylnitrile such as acetonitrile,propionitrile and the like; amide such as N,N-dimethylformamide, andpreferably tetrahydrofuran, acetonitrile or N,N-dimethylformamide. Thetemperature of reaction is conventionally −10 to 200□, preferably 25 to120□, and the reaction time is conventionally 10 minutes-60 hours,preferably 10 minutes-12 hours.

In the above Reaction Scheme 3,

a is a coupling agent (e.g., EDC, CDI, BOP-Cl);

b is PCl₅ or Tf₂O and Ph₃PO;

c is metal hydroxide (e.g., NaOH, LiOH);

d is I₂ or MsCl or the like;

e is Compound (13);

R4 is the same as defined in Reaction Scheme (1);

R12, R13, R14, R15, R16 and Q are the same as defined in Reaction Scheme(2).

Compound (17) may be prepared by the method described in Reaction Scheme(10).

Compound (18) may be prepared by using Compound (6) and Compound (17)according to the synthesis method of Compound (8) in Reaction Scheme(2).

Compound (19) may be prepared by using Compound (18) according to thesynthesis method of Compound (9) in Reaction Scheme (2).

Compound (20) may be prepared by using Compound (19) according to thesynthesis method of Compound (6) in Reaction Scheme (2).

Compound (21) may be prepared by using Compound (20) according to thesynthesis method of Compound (16) in Reaction Scheme (2).

In the above Reaction Scheme (4),

a is SOCl₂ or (COCl)₂; and aqueous NH₄OH solution;

b is Lawesson's reagent;

c is Compound (23);

R2 is the same as defined in formula (1);

R4 is the same as defined in Reaction Scheme (1);

R13 is the same as defined in Reaction Scheme (2);

W is a leaving group, for example, halogen such as chloride, bromide,iodide and the like, or sulfonyl such as methanesulfonyl,p-toluenesulfonyl.

Compound (22) may be prepared by modifying carboxylic acid of Compound(6) to amide and then converting amide to thioamide with Lawesson'sreagent.

The method of modifying carboxylic acid of Compound (6) to amide iscarried out through preparing acid chloride by using thionyl chloride(SOCl₂) or oxalyl chloride ((COCl)₂) and then reacting it with ammoniawater. The use amount of chlorination agent is conventionally 1-10equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (6).The use amount of ammonia water is conventionally 1-5 equivalents. Thereaction may be carried out in an inert solvent such as dichloromethane,dichloroethane, chloroform and the like. The temperature of reaction isconventionally −10 to 200□, preferably −10 to 100□, and reaction time isconventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.

Thioamide group may be prepared by reacting amide with Lawesson'sreagent. The use amount of Lawesson's reagent is conventionally 1-10equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (6).The reaction may be carried out in an inert solvent, for example, ethersuch as tetrahydrofuran, diethyl ether and the like; chloroalkane suchas dichloromethane, dichloroethane, chloroform and the like, aromatichydrocarbon such as benzene, toluene and the like, and preferablytetrahydrofuran or toluene, etc. The temperature of reaction isconventionally −25 to 200□, preferably 25 to 150□, and the reaction timeis conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.

Compound (23) is commercially available or may be prepared by knownmethods such as that disclosed in WO 1999/02501.

Compound (24) may be prepared by the coupling reaction of Compound (22)and Compound (23), with using a base if necessary. The base that can beused is, for example, inorganic base such as sodium carbonate, potassiumcarbonate, cesium carbonate and the like; organic base such asdiisopropylethylamine, DBU and the like, and preferably potassiumcarbonate or cesium carbonate. The use amount of base is conventionally0-10 equivalents, preferably 0-5 equivalents to 1 equivalent of Compound(22). The reaction may be carried out in an inert solvent, for example,ether such as tetrahydrofuran, diethyl ether and the like; alkylnitrilesuch as acetonitrile, propionitrile and the like; amide such asN,N-dimethylformamide, and preferably tetrahydrofuran orN,N-dimethylformamide. The temperature of reaction is conventionally −10to 200□, and the reaction time is conventionally 10 minutes-60 hours,preferably 10 minutes-12 hours.

In the above Reaction Scheme 5,

a is amine Compound (25), a coupling agent (e.g., EDC, CDI, BOP-Cl);

b is Lawesson's reagent;

c is a base (e.g., K₂CO₃, Cs₂CO₃);

R2 is the same as defined in formula (1);

R4 is the same as defined in Reaction Scheme (1);

R13 is the same as defined in Reaction Scheme (2);

W is a leaving group, for example, halogen such as chloride, bromide,iodide and the like, or sulfonyl such as methanesulfonyl,p-toluenesulfonyl and the like.

Compound (25) is commercially available or may be prepared by knownmethods disclosed in literatures (Tetrahydron Letters, 28(48),6068-6072, 1987; or Organic Process Research & Development 10(3),472-480, 2006).

Compound (26) may be prepared by the sequential process of amidesynthesis and thioamide synthesis by using Lawesson's reagent. The amidesynthesis through coupling of Compound (6) and Compound (25) may becarried out according to the method of preparing amide Compound (8) inReaction Scheme (2), and the synthesis of thioamide Compound (26) may becarried out according to the method of preparing Compound (22) inReaction Scheme (4).

Compound (27) may be prepared by the cyclization reaction of Compound(26) by using a base. The base that can be used is potassium carbonate,cesium carbonate, diisopropylethylamine, DBU or the like. The use amountof base is conventionally 1-10 equivalents, preferably 1-5 equivalentsto 1 equivalent of Compound (26). The reaction may be carried out in aninert solvent, for example, ether such as tetrahydrofuran, diethyl etherand the like; alkylnitrile such as acetonitrile, propionitrile and thelike; amide such as N,N-dimethylformamide, and preferablytetrahydrofuran, acetonitrile or N,N-dimethylformamide The temperatureof reaction is conventionally −10 to 200□, preferably 25 to 120□, andthe reaction time is conventionally 10 minutes-60 hours, preferably 10minutes-12 hours.

In the above Reaction Scheme 6,

a is H₂NNH₂,

b is Compound (29),

c is a coupling agent (e.g. CDI, BOP-Cl) and Compound (31),

R2 is the same as defined in formula (1),

R4 is the same as defined in Reaction Scheme (2), and

R12 and R13 is the same as defined in Reaction Scheme (2).

Compound (28) may be prepared by the reaction of Compound (5) withhydrazine. The use amount of hydrazine is conventionally 1-10equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (5).The reaction may be carried out in an inert solvent, for example,tetrahydrofuran, methanol, ethanol and the like. The reactiontemperature is conventionally −10 to 200° C. and preferably 25 to 120°C. The reaction time is conventionally 10 minutes-60 hours andpreferably 10 minutes-12 hours.

As for Compound (29), commercially available one is used.

Compound (30) may be prepared by the coupling reaction of Compound (28)with Compound (29). If necessary, an acid catalyst may be used. The useamount of Compound (29) is conventionally 1-10 equivalents, preferably1-5 equivalents to 1 equivalent of Compound (28). The acid catalyst thatcan be used is selected from inorganic acid such as hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid and the like; organiccarbonic acid such as acetic acid, trifluoroacetic acid and the like;amine acid salt such as ammonium chloride; and Lewis acid such asaluminium chloride. The use amount of acid is conventionally 0.001-5equivalents, preferably 0.01-1 equivalent to 1 equivalent of Compound(29). The reaction may be carried out in an inert solvent, for example,ether such as tetrahydrofuran, diethyl ether and the like; aromatichydrocarbon such as benzene, toluene and the like; saturated hydrocarbonsuch as cyclohexane, hexane and the like; or amide such asN,N-dimethylamide. The reaction temperature is conventionally −10 to200° C. and preferably 25 to 120° C. The reaction time is conventionally10 minutes-60 hours and preferably 10 minutes-12 hours.

Compound (31) is commercially available or may be prepared by the methoddisclosed in US 2004/0019215.

Compound (32) may be prepared by the coupling reaction of Compound (6)with Compound (31) and subsequent dehydration reaction.

The use amount of coupling agent for the coupling reaction isconventionally 1-10 equivalents, preferably 1-3 equivalents to 1equivalent of Compound (6). The reaction may be carried out in an inertsolvent such as tetrahydrofuran or N,N-dimethyl amide. The reactiontemperature is conventionally −10 to 200° C. and preferably 0 to 50° C.The reaction time is conventionally 10 minutes-60 hours and preferably10 minutes-12 hours.

The dehydration reaction after the coupling reaction may be carried outby optionally using an acid catalyst. It may be carried out by themethod for the preparation of Compound (30).

In the above Reaction Scheme (7),

a is sodium nitrate (NaNO₂); tin chloride (SnCl₂),

b is ketone Compound (38), a base (e.g. NaOAc),

c is an acid (e.g., polyphosphoric acid (PPA)),

d is NaNO₂,

e is Compound (42), a base (e.g. NaOH),

R3 is the same as defined in formula (1),

R11, R4 and R12 are the same as defined in Reaction Scheme (1), and

R13 is the same as defined in Reaction Scheme (2).

Compound (36) is commercially available or may be prepared by themethods disclosed in literatures [Heterocycles, 68(11), 285-99, 2006, orBioorganic & Medicinal Chemistry Letters, 14(19), 903-4906, 2004].

Compound (37) is commercially available or may be prepared by modifyingan amine group of Compound (36) to hydrazine group according to themethod disclosed in literature [Journal of the America Chemical Society,198(48), 15374-75, 2006].

Hydrazine compound (37) may be prepared by reacting amine group withNaNO₂ in the presence of hydrochloric acid to obtain diazonium salt(42), and without separation, reducing the diazonium salt by usingSnCl₂. The use amount of NaNO₂ is conventionally 1-10 equivalents,preferably 2-5 equivalents to 1 equivalent of Compound (36). The useamount of SnCl₂ is conventionally 1-10 equivalents, preferably 2-5equivalents to 1 equivalent of Compound (36). The reaction may becarried out in aqueous solution of hydrochloric acid with aconcentration of 1-12N, preferably 4-8N. The reaction temperature isconventionally −10 to 50° C. The reaction time is conventionally 10minutes-60 hours and preferably 10 minutes-6 hours.

As for Compound (38), commercially available one is used.

Hydrazone compound (39) may be prepared by the coupling reaction ofCompound (37) with ketone Compound (38). If Compound (37) is in aneutral form, a base is not used, but if Compound (37) is in an acidform, a base should be used for making a neutral form. The base that canbe used is, for example, metal hydroxide such as sodium hydroxide,lithium hydroxide, etc.; metal carbonate such as sodium bicarbonate,potassium carbonate, etc.; metal acetate such as sodium acetate; or anorganic base such as triethylamine, pyridine, etc. The use amount ofbase is conventionally 1-5 equivalents, preferably 1-2 equivalents to 1equivalent of Compound (37). The reaction may be carried out in an inertsolvent such as tetrahydrofuran, methanol, ethanol, etc. The reactiontemperature is conventionally −10 to 100° C., and the reaction time isconventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.

Compound (39) may be prepared by reacting diazonium salt (41) andCompound (42) in the presence of a base according to Japp-Klingemannrearrangement method disclosed in literature [Organic Process Research &Development, 2, 1988, 214-220]. The use amount of hydrochloric acid forthe preparation of diazonium salt (41) is conventionally 1-10equivalents, preferably 2-4 equivalents to 1 equivalent of Compound(36). The base used for the reaction between Compounds (41) and (42) issodium hydroxide. The use amount of the base is conventionally 1-20equivalents, preferably 1-10 equivalents to 1 equivalent of Compound(42). Aqueous solution of 50% ethanol may be used as a solvent. Thereaction temperature is conventionally −10 to 50° C. The reaction timeis conventionally 10 minutes-60 hours and preferably 10 minutes-12hours.

Compound (40) can be prepared by using an acid catalyst and Compound(39). The acid used in the synthesis is polyphosphoric acid,hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, acetic acid,etc., and preferably poylphosphoric acid.

Polyphosphoric acid may be used alone or in combination with aromatichydrocarbon such as benzene, toluene, etc. The reaction temperature isconventionally −25 to 150° C. The reaction time is conventionally 5minutes-60 hours and preferably 5 minutes-12 hours.

Compound (42) is commercially available or may be prepared by themethods disclosed in literatures [WO 2007040289, WO 200601079 or OrganicLetters 9(3), 397-400, 2007].

d is trimethylsilylacetylene or 2-methyl-3-butyn-2-ol, Pd, Cu(I), a base(e.g., Et₃N or Et₂NH),

e is tetrabutylammonium fluoride (Bu₄NF) or NaOH,

f is Compound (48), Pd(II), Cu(I), a base (e.g., Et₃N or Et₂NH),

g is trifluoroacetic anhydride ((CF₃CO)₂O),

R11 and R4 are the same as defined in Reaction Scheme (1), and

R13 is the same as defined in Reaction Scheme (2).

Compound (36) is commercially available or may be prepared by themethods disclosed in literatures [Heterocycles, 68(11), 285-99, 2006, orBioorganic & Medicinal Chemistry Letters, 14(19), 903-4906, 2004].

Compound (43) may be prepared by iodination reaction of Compound (36).The iodination agent for iodination reaction may be selected fromiodine, iodine monobromide and iodine monochloride, and silver ion, forexample, silver nitrate (AgNO₃), silver carbonate

(AgCO₃), silver sulfate (Ag₂SO₄) etc., may be used together. The useamount of iodination agent is conventionally 1-10 equivalents,preferably 1-3 equivalents to 1 equivalent of Compound (36). The useamount of silver ion is conventionally 0-10 equivalents, preferably 0-3equivalents to 1 equivalent of Compound (36). The reaction may becarried out in an inert solvent, for example, ether such astetrahydrofuran, diethyl ether, etc.; alkylalcohol such as methanol,ethanol, etc.; alkylnitrile such as acetonitrile, propionitril, etc.; oran organic acid such as acetic acid. The reaction temperature isconventionally −10 to 200° C. and preferably 0 to 50° C. The reactiontime is conventionally 10 minutes-60 hours and preferably 10 minutes-12hours.

Compound (44) is commercially available or may be prepared by themethods disclosed in literatures [Synthesis, 59-61, 2004 or Bioorganic &Medicinal Chemistry Letters, 13, 197-209, 2003] or the synthesis methodof Compound (47).

Compound (45) may be prepared by the coupling reaction of iodide groupof Compound (43) and acetylene group of Compound (44) according to themethod disclosed in literature [Tetrahedron, 59, 2003, 1571-1587].

The coupling reaction may be carried out with the use of Pd (0) or Pd(II) catalyst [e.g., Pd(Ph₃P)₄, PdCl₂(Ph₃P)₂)], Cu(I) catalyst (e.g.,CuI) and a base (e.g., triethylamine, diethylamine, etc.). The useamount of Pd catalyst is conventionally 0.001-5 equivalents, preferably0.01-1 equivalent to 1 equivalent of Compound (43). The use amount ofCu(I) catalyst is conventionally 0.001-5 equivalents, preferably 0.01-1equivalent to 1 equivalent of Compound (43). The use amount of base isconventionally 1-10 equivalents, preferably 1-5 equivalents to 1equivalent of Compound (43). The reaction may be carried out in an inertsolvent, for example, ether such as tetrahydrofuran, diethyl lether,etc.; aromatic hydrocarbon such as benzene, toluene, etc.; orN,N-dimethylformamide. The reaction temperature is conventionally −10 to200° C. and preferably 25 to 120° C. The reaction time is conventionally10 minutes-60 hours and preferably 10 minutes-12 hours.

Compound (46) may be prepared by the cyclization reaction of Compound(45) according to the methods disclosed in literatures [JP 2001/233855;Tetrahedron, 59, 2003, 1571-1587; Tetrahedron Letters, 47(36), 2006,6485-6388; or Heterocycles, 64, 2004, 475-482, etc.]. The cyclizationreaction may be carried out by using a base, Cu (I), Pd (II), etc. Thebase that can be used is, for example, potassium hydride (KH), potassiumt-butoxide (KOBu^(t)), etc., and the use amount of base isconventionally 1-10 equivalents, preferably 1-2 equivalents to 1equivalent of Compound (45). The use amount of each of Cu (I) and Pd(II) is conventionally 0.001-5 equivalents, preferably 0.01-1 equivalentto 1 equivalent of Compound (45). The reaction may be carried out in aninert solvent, for example, ether such as tetrahydrofuran, diethylether, etc.; aromatic hydrocarbon such as benzene, toluene, etc.; alkylnitrile such as acetonitrile, propionitrile, etc.; N,N-dimethylformamideor N-methyl-pyrrolidinone (NMP). If a base is used, the preferredsolvent is NMP. If Cu (I) or Pd (II) is used, the preferred solvent isacetonitrile, toluene, N,N-dimethylformamide, etc. The reactiontemperature is conventionally −10 to 200° C. and preferably 0 to 120° C.The reaction time is conventionally 10 minutes-60 hours and preferably10 minutes-12 hours.

Compound (46) may also be prepared by modifying the amine group ofCompound (43) to trifluoroacetamide group and then cyclizing with usingPd (II) according to the method disclosed in literature [Tetrahedron,60, 2006, 10983-10992].

Compound (47) may be prepared by the coupling reaction of Compound (43)and acetylene in the presence of Pd (II), Cu(I) and a base according tothe method disclosed in literature [Journal of Organic Chemistry, 71,2006, 167-175]. The acetylene used is trimethylsilylacetylene or2-methyl-3-butyn-2-ol, and the use amount of acetylene is conventionally1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound(43). The use amount of each of Cu (I) and Pd (II) is conventionally0.001-5 equivalents, preferably 0.01-1 equivalent to 1 equivalent ofCompound (46). The base used is diethylamine, triethylamine,diisopropylethylamine, etc. and the use amount of base is conventionally1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound(43). The reaction may be carried out in an inert solvent, for example,ether such as tetrahydrofuran, diethyl ether, etc., or aromatichydrocarbon such as benzene, toluene, etc. The reaction temperature isconventionally −10 to 200° C. and preferably 0 to 120° C. The reactiontime is conventionally 10 minutes-60 hours and preferably 10 minutes-12hours.

Compound (48) is commercially available or may be prepared by themethods disclosed in literatures [Journal of Organic Chemistry, 70,2005, 6519-6522 or Tetrahedron, 60(48), 2004, 10983-10992].

Compound (7) of the present invention may be prepared by the methodspecifically illustrated in the following Reaction Scheme (9).

In Reaction Scheme (9), Compounds (50), (52) and (54) correspond toCompound (7).

In the above Reaction Scheme (9),

a is p-methoxybenzylchloride (PMBC1) or triphenylmethylchloride (TrCl),a base (e.g., NaOH),

b is alkylalcohol (e.g., methanol, ethanol), acetylchloride orthionylchloride,

c is di-t-butyloxy-dicarbonyl (Boc₂O), a base (e.g., NaOH, K₂CO₃),

d is alkylchloroformate (e.g., EtOCOCl), a base (e.g.,N-methylmorpholine),

e is diazomethane (CH₂N₂), a base (e.g., KOH),

f is silver ion (e.g., silver benzoate),

g is an acid,

h is MsCl, Et₃N,

i is p-methoxybenzylthiol (PMBSH), NaH,

R12 represents C₁-C₆ alkyl, and

R14 represents p-MeOBn or Ph₃C.

Compound (49) may be prepared by protecting thiol group of cysteine withp-methoybenzylchloride (PMBC1) or triphenylmethylchloride (TrCl) in thepresence of a base.

The use amount of PMBC1 or TrCl for the protection of thiol group isconventionally 1-5 equivalents, preferably 1-2 equivalents to 1equivalent of cysteine. The base used is sodium hydroxide, potassiumcarbonate, etc., and its use amount is conventionally 1-5 equivalents,preferably 1-2 equivalents to 1 equivalent of cysteine. The reaction maybe carried out in an inert solvent such as tetrahydrofuran, methanol,ethanol, water, etc. The reaction temperature is conventionally −10 to200° C. and preferably 0 to 50° C. The reaction time is conventionally10 minutes-60 hours and preferably 10 minutes-12 hours.

Compound (51) may be prepared by protecting amine group of Compound (49)with BOC group.

The use amount of Boc₂O for the protection of amine group isconventionally 1-5 equivalents, preferably 1-2 equivalents to 1equivalent of cysteine. The used base is, for example, hydroxide such assodium hydroxide, lithium hydroxide etc.; carbonate such as sodiumcarbonate, sodium bicarbonate, potassium carbonate, cesium carbonate,etc.; an organic base such as diisopropylethylamine, triethylamine,etc., and preferably potassium carbonate, triethylamine, etc. Thereaction may be carried out in an inert solvent such as tetrahydrofuran,methanol, ethanol, water, etc. The reaction temperature isconventionally −10 to 200° C. and preferably 0 to 50° C. The reactiontime is conventionally 10 minutes-60 hours and preferably 10 minutes-12hours.

Compound (50) may be prepared by the esterification of carboxyl group ofCompound (49). The esterification reaction may be carried out with theuse of acetylchloride or thionylchloride in an alkylalcohol solvent. Theuse amount of acetylchloride or thionylchloride is conventionally 1-10equivalents, preferably 1-5 equivalents to 1 equivalent of Compound(49). The reaction temperature is conventionally −25 to 200° C. andpreferably 25 to 100° C. The reaction time is conventionally 10minutes-60 hours and preferably 10 minutes-12 hours.

Compound (52) may be prepared by the method disclosed in literature[Helvetica Chimica Acta, 87, 2004, 3131-3159].

In the presence of 1-2 equivalents of a base (e.g., N-methylmorpholine(NMM), triethylamine, etc.), 1 equivalent of Compound (51) is reactedwith 1-2 equivalents of ethylchloroformate (EtOCOCl) orisobutylchloroformate (^(i)BuOCOCl) in tetrahydrofuran solvent at roomtemperature to obtain an anhydride compound. The obtained anhydridecompound is reacted with 1-5 equivalents of diazomethane and 1-5equivalents of aqueous potassium hydroxide solution in diethyl ethersolvent at 0° C., and then reacted with Ag ion (e.g., silvertrifluoroacetate (CF₃CO₂Ag), silver benzoate, etc.) at room temperaturein the absence of light, to prepare an alkyl ester.

The BOC protection group of the prepared compound may be reacted with anacid (e.g., hydrochloric acid, trifluoroacetic acid) in a solvent suchas dioxane, tetrahydrofuran or dichloromethane at room temperature fordeprotection, and then Compound (52) may be obtained.

Compound (53) may be prepared by the method disclosed in literatures[Synlett, 15, 2005, 2397-2399 or Journal of Organic Chemistry, 66(5),2001, 1919-1923] with using glutamic acid or aspartic acid as a startingmaterial.

Compound (54) may be prepared by modifying an alcohol group of Compound(53) to a leaving group and then reacting with p-methoxybenzylthiol(PMBSH), as in the method for preparation of Compound (21) in ReactionScheme (3).

Compound (53) is reacted with 1-5 equivalents of triethylamine and 1-3equivalents of MsCl in a dichloromethane solvent at 0° C. to obtain asulfonate compound. The sulfonate compound may be reacted at 25 to 100°C. with PMBSNa solution, which is prepared by adding 2-5 equivalents ofNaH and 2-5 equivalents of PMBSH in DMF, to prepare Compound (54).

Compound (17) of the present invention may be prepared by the methodspecifically illustrated in the following Reaction Scheme (10).

In the above Reaction Scheme (10),

a is Boc₂O,

b is a reducing agent (e.g., NaBH₄),

c is t-butylcarbonylchloride (^(t)BuCOCl), a base (e.g., Et₃N),

d is an acid,

R12 represents C₁-C₆ alkyl, and

R14 represents p-MeOBn or Ph₃C.

Compound (17) may be prepared by subsequently protecting an amine groupwith BOC group, reducing ester group to an alcohol, protecting thealcohol group with an ester group, and deprotecting the BOC group.

The protection of amine group may be carried out according to the methodillustrated in Reaction Scheme (9).

The reduction of ester group may be carried out by reacting with 2-5equivalents of lithium borohydride for 1-5 hours in tetrahydrofuransolvent at 0° C.

The protection of alcohol group may be carried out by the reacting witht-BuCOCl for 10 minutes—12 hours in the presence of 1-5 equivalents of abase such as triethylamine or pyridine etc., in dichloromethane solventat 0-25° C.

The deprotection of BOC group may be carried out by dissolving reactantsin an inert solvent such as tetrahydrofuran, dioxane, ethyl acetate ordichloromethane and reacting with 1-10 equivalents of hydrochloric acidor acetic acid for 10 minutes-12 hours at 0 to 50° C.

The compounds, which are not specifically explained about preparationthereof in the present specification, are disclosed compounds per se orthe compounds that may be prepared according to already-known synthesesor similar syntheses thereof.

The compound of formula (1) prepared by the above methods may beseparated or purified from the reaction products by various methods suchas recrystallization, ionic electrophoresis, silica gel columnchromatography or ion exchange resin chromatography, etc.

As explained in the above, the indole or indazole compounds of thepresent invention, starting materials or intermediates, etc. forpreparation thereof may be prepared by various methods.

ADVANTAGEOUS EFFECTS

The composition of the present invention comprising the above-explainedindole or indazole compound of formula (1) as an active component can beused for preserving cells or organs of animals. More specifically, thecomposition of the present invention can be used for preventing injuryof organs, isolated cell systems or tissues caused by cold storage,transplant operation or post-transplantation reperfusion. However, theeffects of the composition according to the present invention are notlimited to those explained above.

“Cell” as used herein means an animal cell isolated from tissues ofhuman or non-human animals and selected from the group consisting ofliver cell, skin cell, mucous membrane cell, Langerhans islet cell,nerve cell, cartilage cell, endothelium cell, epithelial cell, bone celland muscle cell, or sperm, egg or fertilized egg of livestock or fish.“Organ” is selected from the group consisting of skin, cornea, kidney,heart, liver, pancreas, intestine, nerve, lung, placenta, umbilical cordand blood vessel system.

In addition, the indole or indazole compound according to the presentinvention can be used by further adding it in a conventional solutionfor preserving organs. If the indole or indazole compound according tothe present invention is added in the conventional solution forpreserving organs, the preservation period of the above-mentioned organsfor transplantation can be greatly extended and organ damage aftertransplantation can be effectively prevented or treated.

Furthermore, by adding the indole or indazole compound according to thepresent invention in conventional cell-culture medium or preservationsolutions, liver cells or pancreas cells, etc. of animals can bepreserved for a long time even without freezing. Thus, such preservedanimal cells can be utilized for applications in cell or tissueengineering to prepare useful materials.

Together with the active ingredient, the “pharmaceutical composition”according to the present invention may comprise a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof, ifneeded. Such a pharmaceutical composition facilitates the administrationof the compound into a living organism. There are many administrationtechniques including oral, injection, aerosol, parenteral and topicaladministrations, but not limited thereto.

“Carrier” as used herein means a substance which facilitates theincorporation of the compound into cells or tissues. For example,dimethylsulfoxide (DMSO) is a typical carrier which is used tofacilitate the introduction of various organic compounds into cells ortissues of living organisms.

“Diluent” as used herein is defined as a substance being diluted inwater that dissolves the compound, as well as stabilizing the subjectcompound in its biologically active form. The salts dissolved in abuffer solution are utilized as diluents in the art. A typical buffersolution is phosphate-buffered saline which mimics the salt form ofhuman solution. Buffer diluents hardly alter biological activities ofthe compound since the buffer salts can control the pH of solution atlow concentration.

“Pharmaceutically acceptable” as used herein means the property thatdoes not impair biological activities and properties of the compound.

The compounds of the present invention can be formulated in variouspharmaceutical dosage forms according to the desired purpose. For thepreparation of the pharmaceutical composition of the present invention,the active ingredient, specifically the compounds of formula (1),pharmaceutically acceptable salt or isomer thereof, is mixed togetherwith various pharmaceutically acceptable carriers which can be selectedaccording to the formulation to be prepared. For example, according tothe desired purpose, the pharmaceutical composition of the presentinvention can be formulated as injection preparation, oral preparation,etc.

The compounds of the present invention can be formulated by the methodsknown in the art utilizing known pharmaceutical carriers and excipients,and incorporated into containers of unit dose form or multi-dose form.The form of the preparation can be solutions, suspensions or emulsionsin oily or aqueous media, and may contain typical dispersing agents,suspending agents or stabilizers. Further, for example, it can be a formof dry powder which is intended to be reconstructed by dissolving insterilized, pyrogen-free water prior to use. The compounds of thepresent invention also can be formulated into suppository formsutilizing typical suppository base such as cocoa butter or otherglycerides. As solid dosage forms for oral administration, capsules,tablets, pills, powder and granules can be prepared, and capsules andtablets are especially useful. Preferably, tablets and pills areprepared as enteric coated forms. Solid dosage forms can be prepared bymixing the compound of the present invention together with carriers suchas one or more inert diluents such as sucrose, lactose, starch, etc.,lubricants such as magnesium stearate, disintegrant, binder, etc.

If needed, the compound of the present invention or the pharmaceuticalcompositions containing the same can also be administered in combinationwith other active agents, for example, other materials that can preventinjury of organs, isolated cell systems or tissues caused by coldstorage, transplant operation or post-transplantation reperfusion

The dosage of the compounds of formula (1) depends on the prescriptionof a physician, taking into account such factors as body weight and ageof the patient, specific nature of the disease and severity of thedisease, etc. However, dosage needed for transplanting an organ to anadult is typically from about 1 nM to 100 μM, and generally aconcentration of 10 μM or less will be a sufficient dosage but for somepatients, higher dosage may be preferable.

“Treatment” as used herein means interrupting or delaying the progressof the disease when applied to the subject showing the onset of diseasesymptoms and “prevention” means interrupting or delaying the sign of theonset of disease when applied to the subject that does not show but isat risk of the onset of disease symptoms.

The present invention will be more specifically explained by thefollowing preparations and examples. However, it should be understandthat they are intended to illustrate the present invention but not inany manner to limit the scope of the present invention. In the followingpreparations and examples, M means molar concentration, and N meansnormal concentration.

DESCRIPTION OF DRAWINGS

FIG. 1 illustrates a hepatocyte-protecting effect of the compound ofExample 21 according to the present invention through the results ofexperiments using rat primary hepatocytes.

FIG. 2 illustrates a recovery capacity of the compounds of Examples 126,127, 137 and 138 according to the present invention in lung cell LB-HELat 37° C. with the passage of time after cold shock for 24 hours,compared with the control drugs, IM54 and nec-1.

FIG. 3 illustrates a protecting effect of the compound of Example 126according to the present invention against cold preservation injury inrat-isolated perfusion liver model, compared with the conventionalpreservation solution, HTK solution, through the measurement of LDH, ASTand ALT activity.

FIG. 4 illustrates a protecting effect of the compound of Example 126according to the present invention against cold ischemia and warmreperfusion injury in rat-isolated perfusion liver model, compared withthe conventional preservation solution, HTK solution, through themeasurement of LDH activity.

FIG. 5 illustrates a protecting effect of the compound of Example 126according to the present invention against cold ischemia/warmreperfusion injury in rat-isolated perfusion liver model, compared withthe conventional preservation solution, HTK solution, through themeasurement of bile output.

BEST MODE FOR CARRYING OUT THE INVENTION Preparation 1: Synthesis of2-[(4-fluoro-2-nitro-phenyl-)hydrazono]-propionic acid ethyl ester

4-Fluoro-2-nitroaniline (10 g, 64 mmol) was dissolved in 6N hydrochloricacid (64 ml, 0.27 mol), sodium nitrate (4.4 g, 64 mmol) dissolved inwater (50 ml) was slowly added in drops at 0□, and the mixture wasstirred for 30 min at 0□˜room temperature. At the same time, ethyl2-methylacetoacetate (9.2 ml, 64 mmol) and sodium hydroxide (19 g, 0.34mol) were dissolved in 80% ethanol aqueous solution (95 ml) and stirredfor 10 min at 0□. Thus prepared two solutions were mixed and stirred for8 h at 0□˜room temperature. To the reaction mixture was added water. Thesolid not dissolved was collected, washed with water and dried to givethe title compound (7.9 g, Yield 46%).

¹H-NMR (400 HMz, CDCl₃); δ 10.81 (br s, 1H), 8.05 (m, 1H), 7.90 (m, 1H),7.41 (m, 1H), 4.36 (q, 2H), 2.22 (S, 3H), 1.38 (t, 3H)

Preparation 2: Synthesis of 5-fluoro-7-nitro-1H-indole-2-carboxylic acidethyl ester

The compound obtained in Preparation 1 (8.8 g, 33 mmol) was mixed withpolyphosphoric acid (50 ml), and the mixture was stirred for 7 h at 600.To the reaction mixture was added water. The solid not dissolved wascollected, washed with water and dried to give the title compound (3.4g, Yield 41%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.55 (br s, 1H), 8.16 (m, 1H), 8.10 (m,1H), 7.42 (s, 1H), 4.40 (q, 2H), 1.36 (t, 3H)

Preparation 3: Synthesis of (4-chloro-2-nitro-phenyl)-hydrazinehydrochloride

4-Chloro-2-nitroaniline (40 g, 0.23 mol) was dissolved in12N-hydrochloric acid (100 ml). Sodium nitrate (16 g, 0.23 mol)dissolved in water (50 ml) was slowly added in drops at 0□, and themixture was stirred for 30 min at 0□˜room temperature. The temperaturewas lowered to 0□, and tin(II) chloride (132 g, 0.70 mol) dissolved in12N-hydrochloric acid (100 ml) was slowly added in drops. The mixturewas stirred for 3 h at 0□˜room temperature. The resulting yellow solidwas filtered, washed with a small amount of 6N—HCl and dried to give thetitle compound (30 g, Yield, 63%).

¹H-NMR (400 HMz, DMSO-d₆); δ 9.21 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.66(d, J=9.6 Hz, 1H), 7.55 (dd, J=2.4, 9.6 Hz, 1H), 4.74 (br s, 2H)

Preparation 4: Synthesis of2-[(4-chloro-2-nitro-phenyl)-hydrazono]-propionic acid methyl ester

The hydrazine (30 g, 0.14 mol) obtained in Preparation 3 and methylpyruvate (14.4 ml, 0.16 mol) were dissolved in methanol (300 ml), andsodium acetate (14.2 g, 0.17 mol) was added thereto. The mixture wasstirred for 8 h at room temperature. The resulting yellow solid wasfiltered, washed with water and methanol, and dried to give the titlecompound (30 g, Yield 82%).

¹H-NMR (400 HMz, CDCl₃); δ 10.88 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.01(d, J=9.2 Hz, 1H), 7.56 (dd, J=2.4, 9.2 Hz, 1H), 3.90 (s, 3H), 2.23 (s,3H).

Mass spectrum (ESI, m/z): Calculated for C₁₀H₁₀C1N₃O₄: 271.04, Found:271.66

Preparation 5: Synthesis of 5-chloro-7-nitro-1H-indole-2-carboxylic acidmethyl ester

To the compound (13 g, 46 mmol) obtained in Preparation 4 was addedpolyphosphoric acid (100 ml), and the mixture was heated at 100□ for 4h. After completion of the reaction, water was added to the reactionmixture. The solid not dissolved was collected, washed with water anddried to give the title compound (6.0 g, Yield 49%).

¹H-NMR (400 HMz, CDCl₃); δ 10.32 (br s, 1H), 8.29 (d, 1H), 8.03 (d,J=2.4 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 4.01 (s, 3H)

Mass spectrum (ESI, m/z): Calculated: 254.01, Found: 254.63

Preparation 6: Synthesis of 5-bromo-7-nitro-1H-indole-2-carboxylic acidmethyl ester

4-Bromo-2-nitroaniline (15.6 g, 71.9 mmol) was reacted according to thesame procedures as Preparations 3 to 5 to give the title compound (7.2g, Yield 73%).

¹H-NMR (400 HMz, CDCl₃); δ 10.33 (br s, 1H), 8.41 (s, 1H), 8.18 (s, 1H),7.30 (d, J=4.0 Hz, 1H), 4.01 (s, 3H)

Preparation 7: Synthesis of 5-methyl-7-nitro-1H-indole-2-carboxylic acidmethyl ester

4-Methyl-2-nitroaniline (40 g, 0.26 mol) was reacted according to thesame procedures as Preparations 3 to 5 to give the title compound (20 g,Yield 32%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.25 (br s, 1H), 8.08 (3, 1H), 7.96 (s,1H), 7.32 (s, 1H), 3.87 (s, 3H), 2.44 (s, 3H)

Preparation 8: Synthesis of 4-ethoxy-2-nitro-phenylamine

4-Ethoxyaniline (40 g, 0.29 mol) and triethylamine (61 ml, 0.44 mol)were dissolved in dichloromethane (200 ml). Acetic anhydride (30 ml,0.32 mmol) was added in drops, and the mixture was stirred for 1 h at0□˜room temperature. 1 N-hydrochloric acid solution was added thereto,and the resulting mixture was extracted with ethyl acetate, washed withsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate.

Thus obtained acetamide compound was dissolved in dichloromethane (200ml), and fuming nitric acid (13 ml, 0.29 mol) was added in drops at 0□.The resulting mixture was stirred for 1 h at 0□˜room temperature.Saturated aqueous sodium hydrogen carbonate solution was added, and themixture was extracted with ethyl acetate, washed with saturated sodiumchloride solution and dried over anhydrous magnesium sulfate.

Thus obtained nitrate compound was dissolved in methanol (100 ml) andtetrahydrofuran (100 ml), and 6N-sodium hydride was added in drops. Themixture was stirred for 6 h at room temperature. After completion of thereaction, 6N-hydrochloric acid solution was added to neutralize thereaction mixture to about pH 7. The mixture was extracted with ethylacetate, washed with saturated sodium chloride solution and dried overanhydrous magnesium sulfate to give the title compound (44 g, Yield83%).

Preparation 9: Synthesis of 5-ethoxy-7-nitro-1H-indole-2-carboxylic acidmethyl ester

4-Ethoxy-2-nitroaniline obtained in Preparation 8 (40 g, 0.22 mol) wasreacted according to the same procedures as Preparations 3 to 5 to givethe title compound (13 g, Yield 22%).

¹H-NMR (400 HMz, DMSO-d₆); δ 10.20 (br s, 1H), 7.86 (s, 1H), 7.51 (s,1H), 7.26 (s, 1H), 4.13 (m, 2H), 3.98 (s, 3H), 1.47 (m, 3H)

Preparation 10: Synthesis of 7-nitro-5-phenoxy-1H-indole-2-carboxylicacid methyl ester

4-Aminophenyl phenyl ether (20 g, 0.11 mol) was reacted according to thesame procedures as Preparation 8 and Preparations 3 to 5 in the order togive the title compound (5 g, Yield 15%).

¹H-NMR (400 HMz, CDCl₃); δ 10.26 (br s, 1H), 8.05 (s, 1H), 7.69 (s, 1H),7.39 (m, 2H), 7.26 (s, 1H), 7.15 (m, 1H), 7.01 (m, 2H), 4.00 (s, 3H)

Preparation 11: Synthesis of7-nitro-5-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester

(Step 1)

1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g,0.38 mol) were dissolved in N,N-dimethylformamide (100 ml). Potassiumcarbonate (52.6 g, 0.38 mol) was added, and the mixture was stirred for20 h at 100□. Water was added, and the resulting mixture was extractedwith ethyl acetate, washed with saturated sodium chloride solution anddried over anhydrous magnesium sulfate to give3-(4-nitro-phenoxy)-pyridine.

Thus obtained compound was dissolved using water (100 ml),tetrahydrofuran (100 ml) and methanol (100 ml). Iron dust (103 g, 1.84mol) and ammonium chloride (99 g, 1.84 mol) were added, and the mixturewas stirred using a mechanical stirrer for 3 h at 80□. After completionof the reaction, the reaction mixture was filtered through celite,washed with methanol and concentrated. The resulting solid was filtered,washed with ether and dried to give 4-(pyridin-3-yloxy)-phenylamine (17g, Yield 36%).

(Step 2)

4-(Pyridin-3-yloxy)-phenylamine (25 g, 0.13 mol) was reacted accordingto the same procedures as Preparation 8 and Preparations 3 to 5 in theorder to give the title compound (4.2 g, Yield 10%).

¹H-NMR (400 HMz, CDCl₃); δ 10.32 (br s, 1H), 8.51˜8.47 (m, 2H), 8.05 (d,J=2.4 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.42˜7.35 (m, 2H), 7.31 (d, J=2.4Hz, 1H), 4.48 (q, 2H), 1.47 (t, 3H)

Preparation 12: Synthesis of 5-methyl-7-nitro-2-pyridin-2-yl-1H-indole

(4-Methyl-2-nitrophenyl)hydrazine hydrochloride (10 g, 49 mmol) and2-acetylpyridine (5.5 ml, 49 mmol) were reacted according to the sameprocedures as Preparations 4 to 5 to give the title compound (2 g, Yield16%).

¹H-NMR (400 HMz, DMSO-d₆); δ 10.89 (br s, 1H), 8.70 (d, J=4.4 Hz, 1H),8.14 (d, J=8.0 Hz, 1H), 7.98˜7.92 (m, 3H), 7.42˜7.39 (m, 2H), 2.49 (s,3H)

Preparation 13: Synthesis of 5-methyl-7-nitro-2-pyrazin-2-yl-1H-indole

(4-Methyl-2-nitrophenyl)hydrazine hydrochloride (2 g, 9.8 mmol) and2-acetylpyrazine (1.2 ml, 9.8 mmol) were reacted according to the sameprocedures as Preparations 4 to 5 to give the title compound (0.3 g,Yield 19%).

¹H-NMR (500 HMz, CDCl₃) δ 10.64 (br s, 1H), 9.06 (d, J=1.2 Hz, 1H), 8.57(s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 7.12 (d,J=2.4 Hz, 1H), 2.51 (s, 3H)

Preparation 14: Synthesis of 7-nitro-2-pyridin-2-yl-1H-indole

2-Nitrophenylhydrazine hydrochloride (5 g, 26 mmol) and 2-acetylpyridine(2.5 ml, 26 mmol) were reacted according to the same procedures asPreparations 4 to 5 to give the title compound (1 g, Yield 16%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.01 (br s, 1H), 8.72 (d, J=4.0 Hz, 1H),8.15 (m, 3H), 7.93 (m, 1H), 7.49 (s, 1H), 7.42 (m, 1H), 7.30 (m, 1H)

Preparation 15: Synthesis of 7-nitro-2-pyrazin-2-yl-1H-indole

2-Nitrophenylhydrazine hydrochloride (3.1 g, 16 mmol) and2-acetylpyrazine (2.0 ml, 16 mmol) were reacted according to the sameprocedures as Preparations 4 to 5 to give the title compound (0.5 g,Yield 13%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.24 (br s, 1H), 9.46 (d, J=4.0 Hz, 1H),8.76 (m, 1H), 8.65 (d, J=4.0 Hz, 0, 8.20 (dd, J=4.0, 8.0 Hz, 1H), 7.64(d, J=4.0 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H)

Preparation 16: Synthesis of 5-ethoxy-7-nitro-2-pyridin-2-yl-1H-indole

(4-Ethoxy-2-nitrophenyl)hydrazine hydrochloride (5 g, 21 mmol) and2-acetylpyridine (2.4 ml, 21 mmol) were reacted according to the sameprocedures as Preparations 4 to 5 to give the title compound (0.5 g,Yield 8%).

¹H-NMR (400 HMz, CDCl₃); δ 10.97 (br s, 1H), 8.60 (m, 1H), 7.79 (m, 1H),7.73 (m, 1H), 7.61 (d, J=2.8 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.24 (m,1H), 7.02 (d, J=2.4 Hz, 1H), 4.03 (q, 2H), 1.45 (t, 3H)

Preparation 17: Synthesis of 7-nitro-5-phenoxy-2-pyridin-2-yl-1H-indole

(4-Phenoxy-2-nitrophenyl)hydrazine hydrochloride (10 g, 49 mmol) and2-acetylpyridine (5.5 ml, 49 mmol) were reacted according to the sameprocedures as Preparations 4 to 5 to give the title compound (2 g, Yield16%).

¹H-NMR (400 HMz, CDCl₃); δ 10.86 (br s, 1H), 8.68 (d, J=4.8 Hz, 1H),7.92 (d, J=2.0 Hz, 1H), 7.84˜7.76 (m, 2H), 7.65 (d, J=2.0 Hz, 1H), 7.36(m, 3H), 7.28 (m, 1H), 7.13 (m, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.03 (s,1H), 7.02 (s, 1H)

Preparation 18: Synthesis of 3,5-dimethyl-7-nitro-2-phenyl-1H-indole

(4-Methyl-2-nitrophenyl)hydrazine hydrochloride (1.0 g, 4.9 mmol) and2-propiophenone (0.7 ml, 4.9 mmol) were reacted according to the sameprocedures as Preparations 4 to 5 to give the title compound (150 mg,Yield 11%).

Preparation 19: Synthesis of 5-methyl-7-nitro-2-phenyl-1H-indole

(Step 1)

4-Methyl-2-nitroaniline (20 g, 131.5 mmol) was dissolved in ethanol (300ml), silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol)were added, and the mixture was stirred for 8 h at room temperature.After completion of the reaction, the reaction mixture was filteredthrough celite, washed with ethyl acetate (100 ml) and concentrated.Water was added, and the mixture was extracted with ethyl acetate,washed with saturated sodium chloride solution and dried over anhydrousmagnesium sulfate to give 2-iodo-4-methyl-6-nitro-phenylamine (29 g,Yield 69%).

¹H-NMR (500 MHz, CDCl₃); δ 7.94 (s, 1H), 7.75 (s, 1H), 6.48 (br s, 2H),2.23 (s, 3H)

(Step 2)

The compound obtained in Step 1 (7 g, 25.2 mmol) and phenylacetylene(3.3 ml, 30, 22 mmol) were dissolved in tetrahydrofuran (100 ml),triethylamine (11 ml, 75.5 mmol),dichloro(bistriphenylphosphine)palladium(II) (1.8 g, 2.52 mmol) andcupper(I) iodide (0.48 g, 2.52 mmol) were added, and the mixture wasstirred for 8 h at room temperature. After completion of the reaction,water was added. The mixture was extracted with ethyl acetate, washedwith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate and purified by column chromatography to give4-methyl-2-nitro-6-phenylethinyl-phenylamine (4.5 g, Yield 71%).

¹H-NMR (400 HMz, CDCl₃); δ 7.93 (s, 1H), 7.53 (m, 2H), 7.46 (s, 1H),7.39 (m, 3H), 6.62 (br s, 2H), 2.26 (s, 3H)

(Step 3)

The compound obtained in Step 2 (4.5 g, 17.8 mmol) was dissolved intetrahydrofuran (120 ml) and N-methyl-pyrrolidinone (30 ml). Potassiumt-butoxide (4 g, 35.7 mmol) was added, and the mixture was stirred for 3h at room temperature. After completion of the reaction, water wasadded. The mixture was extracted with ethyl acetate, washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate and purified by column chromatography to give5-methyl-7-nitro-2-phenyl-1H-indole (1.0 g, Yield 22%).

¹H-NMR (400 HMz, CDCl₃); δ 11.53 (br s, 1H), 8.02 (d, J=7.6 Hz, 1H),7.94 (s, 1H), 7.87 (s, 1H), 7.50 (m, 2H), 7.41 (m, 1H), 7.09 (m, J=2.0Hz, 1H), 2.49 (s, 3H)

Preparation 20: Synthesis of 2-cyclohexyl-5-methyl-7-nitro-1H-indole

6-Iodo-4-methyl-2-nitroaniline (500 mg, 1.8 mmol) andcyclohexylacetylene (0.23 ml, 1.8 mmol) were reacted according to thesame procedure as Preparation 19 to give the title compound (290 mg,Yield 62%).

¹H-NMR (500 HMz, CDCl₃); δ 9.34 (br s, 1H), 7.88 (s, 1H), 7.63 (s, 1H)6.26 (s, 1H), 2.76 (m, 1H), 2.47 (s, 3H), 2.10 (m, 2H), 1.87 (m, 2H),1.78 (m, 1H), 1.52˜1.42 (m, 4H), 1.31 (m, 1H)

Preparation 21: Synthesis of5-methyl-2-(6-methyl-pyridin-2-yl)-7-nitro-1H-indole

6-Iodo-4-methyl-2-nitroaniline (500 mg, 1.8 mmol) and2-ethinyl-6-methylpyridine (210 mg, 1.8 mmol) were reacted according tothe same procedure as Preparation 19 to give the title compound (170 mg,Yield 35%).

¹H-NMR (500 HMz, CDCl₃); δ 10.77 (br s, 1H), 7.98 (s, 1H), 7.73 (s, 1H),7.64˜7.58 (m, 2H), 7.08 (d, J=7.4 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 2.62(s, 3H), 2.50 (s, 3H)

Preparation 22: Synthesis of(R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl esterhydrochloride

(Step 1)

To a mixed solution of diethyl ether (400 ml) and conc. hydrochloricacid (400 ml) was added in drops 4-methoxybenzyl chloride (280 g, 1780mmol) dissolved in diethyl ether (400 ml) for 2 h, and the mixture wasstirred for 1 h. The organic layer was separated and added to a solutionwhich was prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2Naqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). Themixture was stirred for 2 h at room temperature. After completion of thereaction, the mixture was cooled to 0□, and neutralized to pH 7 using 3Naqueous hydrochloric acid solution. The resulting solid was filtered anddried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid(250 g, 1035 mmol, Yield 64%).

(Step 2)

The compound obtained in Step 1 (30.7 g, 127.3 mmol) was dissolved intetrahydrofuran (150 ml) and water (150 ml). Potassium carbonate (26.4g, 190 mmol) and di-t-butyloxy-dicarbonyl (27.7 g, 127.3 mmol) wereadded, and the mixture was stirred for 2 h at room temperature. Aftercompletion of the reaction, the mixture was distilled under reducedpressure to remove tetrahydrofuran. The mixture was cooled to 0□, andacidified to pH 3 using 3N aqueous hydrochloric acid solution. Theresulting solid was washed with water and dried to give(R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propionic acid(43 g, 126 mmol, Yield 99%).

(Step 3)

The compound obtained in Step 2 (43 g), 1-methylmorpholine (14.5 ml, 132mmol) and ethyl chloroformate (14.1 ml, 132 mmol) were dissolved intetrahydrofuran (500 ml), and the mixture was stirred for 1 h at −25□.At the same time, potassium hydroxide (75 g, 1336 mmol) was dissolved inwater (75 ml) and diethylether (750 ml), N-methyl-nitrosourea (26 g, 252mmol) was added in drops for 2 h at 0□, and the mixture was stirred for30 min. Thus prepared two solutions were mixed and stirred for 3 h at−25□˜room temperature. After completion of the reaction, water wasadded. The mixture was washed with saturated sodium hydrogen carbonateaqueous solution and saturated ammonium chloride aqueous solution in theorder. The organic layer was concentrated to give[(R)-3-diazo-1-(4-methoxy-benzylsulfanylmethyl)-2-oxo-propyl]-carbamicacid t-butyl ester.

¹H-NMR (400 HMz, CDCl₃); δ 7.25 (d, J=8.8 Hzm 2H), 6.86 (d, J=8.8 Hz,2H), 5.48 (br s 1H), 5.29 (m, 1H), 4.31 (m, 1H), 3.79 (s, 3H), 3.69 (s,2H), 2.76 (d, J=6.0 Hz, 2H), 1.45 (s, 9H)

(Step 4)

The compound obtained in Step 3 was dissolved in methanol (1000 ml),silver benzoate (7.1 g, 31.1 mmol) was added, and the mixture wasreacted for 1 h under sonication. After completion of the reaction, themixture was concentrated and purified by column chromatography to give(R)-3-t-butoxycarbonylamino-4-(4-methoxy-benzylsulfanyl)-butyric acidmethyl ester (35.2 g, 95.3 mmol, Yield 76%).

¹H-NMR (500 HMz, CDCl₃); δ 7.24 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz,2H), 5.09 (m, 1H), 4.08 (m, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 3.66 (s,3H), 2.70˜2.52 (m, 4H), 1.44 (s, 9H)

(Step 5)

The compound obtained in Step 4 (35.2 g) was dissolved indichloromethane (70 ml), 4N hydrochloric acid/1,4-dioxane solution (71ml) was added, and the mixture was stirred for 2 h at room temperature.After completion of the reaction, the mixture was concentrated. Thesolid produced by adding dichloromethane (30 ml) and diethylether (150ml) was filtered and dried to give the title compound (25.5 g, 83.3mmol, Yield 87%).

¹H NMR (400 MHz, DMSO-d₆); δ 8.21 (br s, 3H), 7.25 (d, 2H), 6.83 (d,2H), 3.78 (s, 3H), 3.68 (s, 2H), 3.65 (s, 3H), 3.29 (m, 1H), 2.51-2.48(m, 2H), 2.35-2.31 (m, 2H)

Preparation 23: Synthesis of(R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid ethyl esterhydrochloride

L-cysteine (50 g, 0.41 mol) was reacted according to the same procedureas Preparation 22 except that ethanol was used instead of methanol inStep 4 of Preparation 22 to give the title compound (5.2 g, Yield 40%).

¹H NMR (400 MHz, CDCl₃); δ 8.37 (br s, 3H), 7.28 (d, J=8.0 Hz, 2H), 6.87(d, J=8.0 Hz, 2H), 4.11 (m, 2H), 3.73 (s, 3H), 3.70 (s, 2H), 2.81˜2.67(m, 4H), 1.18 (t, 3H)

Preparation 24: Synthesis of(R)-4-amino-5-(4-methoxy-benzylsulfanyl)-pentanoic acid ethyl esterhydrochloride

(Step 1)

(R)-4-t-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester (36 g,137.8 mmol) which can be obtained by a known method and triethylamine(38.4 ml, 275.5 mol) were dissolved in dichloromethane (200 ml).Methanesulfonylchloride (11.7 ml, 151.5 mmol) was added in drops, andthe mixture was stirred for 1 h at 0□˜room temperature. 1N hydrochloricacid solution was added. The mixture was extracted with ethyl acetate,washed with saturated sodium chloride solution and dried over anhydrousmagnesium sulfate to give(R)-4-t-butoxycarbonylamino-5-methanesulfonyloxy-pentanoic acid ethylester.

(Step 2)

The compound obtained in Step 1 and sodium hydride (5.5 g, 137.8 mmol)were added in drops to 4-methoxybenzylmercaptan (15.4 ml, 110.2 mmol)dissolved in N,N-dimethylformamide (150 ml) and stirred for 10 min at0□. The mixture was stirred for 4 h at 0□. After completion of thereaction, water was added. The mixture was extracted with ethyl acetate,washed with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate and purified by column chromatography to give(R)-4-t-butoxycarbonylamino-5-(4-methoxy-benzylsulfanyl)-pentanoic acidethyl ester (21.0 g, Yield 38%).

¹H-NMR (400 HMz, CDCl₃); δ 7.25 (d, J=8.8 Hz, 2H), 6.85 (d, J=88 Hz,2H), 4.56 (m, 1H), 4.12 (m, 2H), 3.79 (s, 3H), 3.69 (s, 2H), 2.53 (m,2H), 2.33 (t, 2H), 1.93 (m, 1H), 1.70 (m, 1H), 1.44 (s, 9H), 1.25 (t,3H)

(Step 3)

The compound obtained in Step 2 (11 g, 62.7 mmol) was dissolved indichloromethane (200 ml), and 4N hydrochloric acid/ethyl acetatesolution (20 ml) was added. The mixture was stirred for 2 h at roomtemperature. After completion of the reaction, the mixture wasthoroughly concentrated, and diethylether (150 ml) was added. Theresulting solid was filtered and dried to give the title compound (20 g,Yield 96%).

¹H NMR (400 MHz, DMSO-d₆); δ 8.69 (br s, 3H), 7.29 (d, J=8.0 Hz, 2H),6.89 (d, J=8.0 Hz, 2H), 4.08 (m, 2H), 3.74 (m, 5H), 3.26 (m, 1H),2.76˜2.63 (m, 2H), 2.49˜2.40 (m, 2H), 1.89 (m, 2H), 1.20 (t, 3H)

Preparation 25: Synthesis of(S)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid isopropyl esterhydrochloride

The same procedure as Preparation 24 was carried out except that(S)-3-t-butoxycarbonylamino-4-hydroxy-butyric acid isopropyl ester (22.0g, 84.2 mmol) was used instead of(R)-4-t-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester to givethe title compound (21.0 g, Yield 75%).

¹H NMR (400 MHz, MeOH-d₄); δ 7.31 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz,2H), 5.06 (m, 1H), 3.80 (s, 3H), 3.78 (s, 2H), 3.60 (m, 1H), 2.81˜2.63(m, 4H), 1.28 (dd, 6H)

Preparation 26: Synthesis of(R)-2-amino-3-(4-methoxy-benzylsulfanyl)propionic acid ethyl esterhydrochloride

The acid compound obtained in Step 1 of Preparation 22 (20 g, 83 mmol)was dissolved in ethanol (100 ml). Acetyl chloride (12 ml, 166 mmol) wasadded in drops, and the mixture was stirred for 12 h at 50□. Aftercompletion of the reaction, the mixture was thoroughly concentrated, anddiethylether was added thereto. The resulting solid was filtered anddried to give the title compound (16.8 g, Yield 69%).

¹H NMR (400 MHz, CDCl₃); δ 8.85 (br s, 3H), 7.27 (d, J=8.0 Hz, 2H), 6.80(d, J=8.0 Hz, 2H), 4.47 (m, 1H), 3.78˜3.69 (m, 8H), 3.17 (m, 2H)

Preparation 27: Synthesis of (R)-2,2-dimethyl-propionic acid2-amino-3-(4-methoxy-benzylsulfanyl)-propyl ester

(Step 1)

The compound obtained in Step 1 of Preparation 22 (50 g, 207.2 mmol) wasdissolved in methanol (300 ml). Acetyl chloride (21 ml, 207.2 mmol) wasadded in drops, and the mixture was stirred for 12 h at 50□. Aftercompletion of the reaction, the mixture was thoroughly concentrated, anddiethylether was added thereto. The resulting solid was filtered anddried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acidmethyl ester.

¹H NMR (400 MHz, DMSO-d₆, HCl salt); δ 8.81 (br s, 3H), 7.29 (d, J=8.4Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 4.28 (m, 1H), 3.18 (br s, 8H), 2.95 (m,2H)

(Step 2)

To the compound obtained in Step 1 were added tetrahydrofuran (200 ml)and water (200 ml) to dissolve. Triethylamine (87 ml, 621.6 mmol) wasadded, and di-t-butyloxy-dicarbonyl (43.0 g, 196.8 mmol) dissolved intetrahydrofuran (100 ml) was added in drops while stirring. The mixturewas stirred for 8 h at room temperature. After completion of thereaction, water was added. The mixture was extracted with ethyl acetate,washed with saturated sodium chloride solution and dried over anhydrousmagnesium sulfate to give(R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propionic acidmethyl ester.

(Step 3)

The compound obtained in Step 2 was dissolved in tetrahydrofuran (300ml). Lithium borohydride (9.0 g, 414.4 mmol) was added, and the mixturewas stirred for 3 h at 0□. After completion of the reaction, water wasadded. The mixture was extracted with ethyl acetate, washed withsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate to give[(R)-2-hydroxy-1-(4-methoxy-benzylsulfanylmethyl)-ethyl]-carbamic acidt-butyl ester.

¹H NMR (500 MHz, DMSO-d₆); δ 7.24 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz,2H), 4.96 (br s, 1H), 3.78 (s, 3H), 3.76 (br s, 1H), 3.70 (s, 2H),3.7˜3.66 (m, 3H), 2.58 (m, 2H), 1.44 (s, 9H)

(Step 4)

The alcohol compound obtained in Step 3 was dissolved in dichloromethane(300 ml). Triethylamine (58 ml, 414.4 mmol) and trimethylacetylchloride(28 ml, 227.9 mmol) were added, and the mixture was stirred for 6 h at0□. After completion of the reaction, water was added. The mixture wasextracted with ethyl acetate, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and purified by columnchromatography to give 2,2-dimethyl-propionic acid(R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propyl ester(81.0 g, Yield 95%).

¹H NMR (400 MHz, CDCl₃); δ 7.25 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz,2H), 4.71 (m, 1H), 4.11 (m, 2H), 3.79 (s, 3H), 3.70 (s, 2H), 2.55 (d,J=6.4 Hz, 2H), 1.52 (s, (H, 1.27 (, 9H)

(Step 5)

The trimethyl acetate compound obtained in Step 4 (81 g, 196 mmol) wasdissolved in dichloromethane (300 ml). 4N-hydrochloric acid/1,4-dioxanesolution (100 ml) was added, and the mixture was stirred for 8 h at roomtemperature. After completion of the reaction, the mixture wasthoroughly concentrated, and diethylether was added thereto. Theresulting solid was filtered and dried to give the title compound (68 g,Yield 95%).

¹H NMR (400 MHz, DMSO-d₆, free form); δ 7.24 (d, J=12.0 Hz, 2H), 6.85(dd, J=4.0, 8.0 Hz, 2H), 4.04 (m, 1H), 3.95 (m, 1H), 3.80 (s, 3H), 3.68(s, 2H), 3.10 (m, 1H), 2.60 (m, 1H), 2.36 (m, 1H), 1.18 (s, 9H)

Preparation 28: Synthesis of2-(4,5-dihydro-thiazol-2-yl)-1H-indole-7-ylamine

(Step 1)

Ethyl 7-nitroindole-2-carboxylate (500 mg, 2.14 mmol) was dissolved in asolvent mixture of tetrahydrofuran and water (1:1, 20 ml), and lithiumhydroxide hydrate (448 mg, 10.7 mmol) was added. The mixture was stirredfor 8 h at room temperature, and 1 N-hydrochloric acid solution wasadded thereto. The mixture was extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate and filtered. The filtratewas distilled under reduced pressure to give7-nitro-1H-indole-2-carboxylic acid.

(Step 2)

The compound obtained in Step 1 and 2-chloroethylamine hydrochloride(371 mg, 3.2 mmol) were dissolved in N,N-dimethylformamide (10 ml).Triethylamine (0.6 ml, 4.3 mmol), EDC (614 mg, 3.2 mmol) and HOBT (433mg, 3.2 mmol) were added. The mixture was stirred for 8 h at roomtemperature, and 1N-hydrochloric acid solution was added. The mixturewas extracted with ethyl acetate, washed with saturated sodiumbicarbonate solution, dried over anhydrous magnesium sulfate andfiltered. The filtrate was distilled under reduced pressure to give7-nitro-1H-indole-2-carboxylic acid (2-chloro-ethyl)-amide.

¹H NMR (400 MHz, CDCl₃); δ 10.51 (br s, 1H), 8.28 (d, J=6.4 Hz, 1H),8.02 (d, J=6.4 Hz, 1H), 7.27 (t, 1H), 7.03 (s, 1H), 6.62 (br s, 1H),3.86 (m, 2H), 3.77 (m, 2H)

(Step 3)

The compound obtained in Step 2 was dissolved in dichloroethane (10 ml)and toluene (10 ml), and Lawesson's reagent (1.29 g, 3.2 mmol) wasadded. The mixture was refluxed for 4 h, and distilled under reducedpressure. Water was added to the residue, and the mixture was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate and filtered.The filtrate was distilled under reduced pressure and the concentratewas purified by column chromatography to give the product of cyclizationreaction, i.e., the compound2-(4,5-dihydro-thiazol-2-yl)-7-nitro-1H-indole (100 mg, Yield 22%).

¹H-NMR (400 HMz, CDCl₃); δ 10.49 (br s, 1H), 8.24 (d, J=8.0 Hzm 1H),7.98 (d, J=7.6 Hz, 1H), 7.23 (t, 1H), 7.02 (s, 1H), 4.47 (t, 2H), 3.51(t, 2H)

(Step 4)

The thiazoline compound obtained in Step 3 was dissolved in methanol (50ml). 10% Pd/C was added, and the mixture was stirred for 8 h underhydrogen gas. After completion of the reaction, the mixture was filteredthrough cellite, distilled under reduced pressure and purified by columnchromatography to give the title compound (80 mg, Yield 91%).

¹H-NMR (400 HMz, CDCl₃); δ 9.78 (br s, 1H). 7.15 (d, J=8.0 Hz, 1H), 6.95(t, J=8.0 Hz, 1H), 6.90 (d. J=1.6 Hz, 1H), 6.60 (dd, 1H), 4.44 (dd, 2H),3.45 (dd, 2H)

Mass spectrum (ESI, m/z): Calculated: 217.07, Found: 217.29

Example 1 Synthesis ofcyclopentyl-[2-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-amine

Cyclopentyl-[2-(4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine

The compound obtained in Preparation 28 (15 mg, 0.07 mmol) was dissolvedin 1,2-dichloroethane (10 ml). Cyclopentanone (12 mg, 0.14 mmol) andsodium triacetoxyborohydride (29 mg, 0.14 mmol) were added, and themixture was stirred for 3 h at room temperature. After completion of thereaction, water was added. The mixture was extracted with ethyl acetate,dried over anhydrous magnesium sulfate and filtered. The filtrate wasdistilled under reduced pressure and the residue was purified by columnchromatography to give the title compound (6.7 mg, Yield 34%).

¹H-NMR (400 HMz, CDCl₃); δ 10.27 (s, 1H), 7.06 (d, J=8.0 Hz, 1H), 7.00(t, J=7.6 Hz, 1H), 6.92 (s, 1H), 6.52 (d, J=7.2 Hz, 1H), 4.42 (m, 2H),4.38 (m, 1H), 4.35 (m, 2H), 2.00 (m, 2H), 1.64 (m, 4H), 1.46 (m, 2H)

Mass spectrum (ESI, m/z): Calculated: 285.13, Found: 285.41

Example 2 Synthesis of[2-(4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-(4-methyl-cyclohexyl)-amine

[2-(4,5-Dihydro-thiazol-2-yl)-1H-in dol-7-yl]-(4-methyl-cyclohexyl)-amine

The compound obtained in Preparation 28 (19 mg, 0.09 mmol) and4-methyl-cyclohexanone were reacted according to the same procedure asExample 1 to give the two diastereomers in the amount of 9.1 mg and 7.4mg (total Yield 60%), respectively.

¹H-NMR (400 HMz, CDCl₃);

Compound 1: δ 10.26 (s, 1H), 7.05˜6.97 (m, 2H), 6.92 (s, 1H), 6.51 (d,J=7.6 Hz, 1H), 4.40 (m, 2H), 3.65 (m, 1H), 3.46 (m, 2H), 1.72 (m, 3H),1.52 (m, 3H), 1.22 (m, 3H), 0.82 (d, J=8.0 Hz, 3H)

Compound 2: δ 10.24 (s, 1H), 7.05˜6.96 (m, 2H), 6.92 (s, 1H), 6.50 (d,J=6.8 Hz, 1H), 4.44 (m, 2H), 3.47 (m, 2H), 3.25 (m, 1H), 2.11 (m, 2H),1.74 (m, 2H), 1.36 (m, 1H), 1.10 (m, 4H), 0.90 (d, J=6.4 Hz, 1H)

Mass spectrum (ESI, m/z): Calculated: 313.16, Found: 313.47

Example 3 Synthesis of[2-(4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-piperidin-4-yl-amine

[2-(4,5-Dihydro-thiazol-2-yl)-1H-in dol-7-yl]-piperidin-4-yl-amine

To the compound prepared from the compound of Preparation 28 (20 mg,0.09 mmol) and 1-(t-butylcarbonyl)-4-piperidone according to the sameprocedure as Example 1 were added dichloromethane andtrifluorocarboxylic acid solution (5:1, v/v, 5 ml). The mixture wasstirred for 1 h at room temperature and distilled under reducedpressure. Saturated sodium bicarbonate solution was added, and themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate and filtered. The filtrate was distilled under reduced pressureand purified by column chromatography to give the title compound (4.9mg, Yield 18%).

¹H-NMR (400 HMz, CDCl₃, MeOH-d₄); δ 7.39 (s, 1H), 7.07 (d, J=8.0 Hz,1H), 6.99 (t, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.47 (d, J=7.6 Hz, 1H), 4.41(m, 2H), 3.77 (m, 1H), 3.48 (m, 4H), 3.11 (m, 2H), 2.29 (m, 2H), 1.87(m, 2H)

Mass spectrum (ESI, m/z): Calculated: 300.14, Found: 300.43

Preparation 29: Synthesis of7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-carboxylic acid

Ethyl 7-nitroindole-2-carboxylate (2.5 g, 10.7 mmol) was dissolved inmethanol (50 ml). 10% Pd/C (200 mg) was added, and the mixture wasstirred for 1 h under hydrogen gas. The mixture was filtered throughcelite, and the filtrate was distilled under reduced pressure. Thedistillate was dissolved 1,2-dichloroethane (50 ml), andtetrahydro-4H-pyran-4-one (1.3 ml, 12.8 mmol) and sodiumtriacetoxyborohydride (3.4 g, 16.1 mmol) were added. The mixture wasstirred for 8 h at room temperature. After completion of the reaction,water was added. The mixture was extracted with ethyl acetate, driedover anhydrous magnesium sulfate and filtered. The filtrate wasdistilled under reduced pressure and concentrated. The residue waspurified by column chromatography. Thus obtained compound was dissolvedin methanol (50 ml) and tetrahydrofuran (50 ml), 1N-sodium hydroxide (43ml, 42.8 mmol) was added, and the mixture was stirred for 8 h at roomtemperature. 1N-hydrochloric acid solution was added, and the mixturewas extracted with ethyl acetate, dried over anhydrous magnesium sulfateand filtered. The filtrate was distilled under reduced pressure to givethe title compound (2.1 g, Yield 76%).

¹H-NMR (400 HMz, DMSO-d₆); δ 12.87 (br s, 1H), 11.46 (s, 1H), 6.97 (d.J=2.0 Hz, 1H), 6.86 (d, J=1.6 Hz, 1H), 6.85 (s, 1H), 6.37 (m, 1H), 5.73(br s, 1H), 3.90 (m, 2H), 3.61 (m, 1H), 3.50 (m, 2H), 2.00 (m, 2H), 1.48(m, 2H)

Mass spectrum (ESI, m/z): Calculated: 260.12, Found: 260.30

Preparation 30: Synthesis of{5-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-[1,2,4]oxadiazol-3-yl}aceticacid ethyl ester

The compound obtained in Preparation 29 (300 mg, 1.15 mmol) wasdissolved in dimethylformamide (20 ml). Ethyl3-(hydroxyamino)-3-iminopropionate (202 mg, 1.38 mmol), EDC (265 mg,1.38 mmol) and HOBT (187 mg, 1.38 mmol) were added thereto. The mixturewas stirred for 8 h at room temperature, and saturated sodiumbicarbonate solution was added. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled under reduced pressure and concentrated. Theresidue was purified by column chromatography. Thus obtained compoundwas dissolved in toluene (20 ml) and dichloroethane (10 ml). The mixturewas refluxed for 8 h at 120□, distilled under reduced pressure andpurified by column chromatography to give the title compound (80 mg,Yield 19%).

¹H-NMR (500 HMz, CDCl₃); δ 9.71 (br s, 1H), 7.35 (d, =1.8 Hz, 1H), 7.15(d, J=8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.25(m, 2H), 4.10 (m, 2H), 3.92 (s, 2H), 3.69 (m, 1H), 3.59 (m, 2H), 2.10(m, 2H), 1.64 (m, 2H), 1.29 (t, 3H)

Mass spectrum (ESI, m/z): Calculated: 370.16, Found: 370.41

Example 4 Synthesis of2-5-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-[1,2,4]oxadiazol-3-yl}-ethanol

2-{5-[7-(Tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-[1,2,4]oxadiazol-3-yl}-ethanol

The compound obtained in Preparation 30 (20 mg, 0.05 mmol) was dissolvedin tetrahydrofuran (2 ml), and lithium borohydride (2.4 mg, 0.10 mmol)was added. The mixture was stirred for 2 h at room temperature, andsaturated ammonium chloride solution was added. The mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and filtered. The filtrate was distilled under reducedpressure and purified by column chromatography to give the titlecompound (4.7 mg, Yield 27%).

¹H-NMR (500 HMz, CDCl₃); δ 10.40 (s 1H), 7.27 (s 1H), 7.08 (d, J=8.0 Hz,1H), 7.04 (t, J=8.0 Hz, 1H), 6.55 (d, J=7.4 Hz, 1H). 4.11 (m. 4H). 3.70(m, 1H), 3.61 (t, 2H), 3.06 (m, 2H), 2.14 (m, 2H), 1.66 (m, 2H)

Mass spectrum (ESI, m/z): Calculated: 328.15, Found: 328.37

Preparation 31: Synthesis of 2,2-dimethyl-propionic acid(R)-2-(7-amino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester

(Step 1)

The 7-nitroindole-carboxylic acid compound obtained in Step 1 ofPreparation 28 (8.2 g, 22.7 mmol) and the amine compound obtained inPreparation 27 (13.2 g, 27.2 mmol) were dissolved in dimethylformamide(100 ml), and EDC (6.6 g, 25.0 mmol) and HOBT (4.6 g, 25.0 mmol) wereadded. The mixture was stirred for 8 h at room temperature, andsaturated sodium bicarbonate solution was added. The mixture wasextracted with ethyl acetate, dried over anhydrous magnesium sulfate andfiltered. The filtrate was distilled under reduced pressure andconcentrated. The residue was purified by column chromatography to give2,2-dimethyl-propionic acid(R)-3-(4-methoxy-benzylsulfanyl)-2-R7-nitro-1H-indole-2-carbonyl)-amino-propylester (8.1 g, Yield 71%).

¹H-NMR (400 HMz, CDCl₃); δ 10.47 (br s, 1H), 8.27 (d, J=8.0 Hz, 1H),8.01 (d, J=8.0 Hz, 1H), 7.26 (m, 2H), 6.93 (d, J=4.0 Hz, 1H), 6.83 (m,2H), 6.74 (d, J=8.0 Hz, 1H), 4.56 (m, 1H), 4.44 (m, 1H), 4.24 (m, 1H),3.74 (m, 5H), 2.77 (m, 1H), 2.62 (m, 1H), 1.18 (s, 9H)

(Step 2)

The compound obtained in Step 1 (1.6 g, 3.2 mmol) was dissolved indichloromethane (50 ml). Phosphorus pentachloride (1.3 g, 6.4 mmol) wasadded, and the mixture was stirred for 5 h at room temperature. Aftercompletion of the reaction, saturated sodium bicarbonate solution wasadded. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate and filtered. The filtrate was distilledunder reduced pressure and concentrated. The residue was purified bycolumn chromatography to give 2,2-dimethyl-propionic acid(R)-2-(7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester (0.8g, Yield 69%).

¹H-NMR (400 HMz, CDCl₃); δ 10.53 (br s, 1H), 8.26 (d, J=8.0 Hz, 1H),7.99 (d, J=8.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H),4.78 (m, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 3.59 (m, 1H), 3.36 (m, 1H),1.20 (s, 9H)

(Step 3)

The compound obtained in Step 2 (2.7 g, 7.5 mmol) was dissolved in asolvent mixture of tetrahydrofuran, methanol and water (1:1:1, 150 ml).Iron dust (4.2 g, 74.7 mmol) and ammonium chloride (4.0 g, 74.7 mmol)were added, and the mixture was stirred using a mechanical stirrer for30 min at 60□. After completion of the reaction, water was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate and filtered. The filtrate was distilled under reduced pressureand purified by column chromatography to give the title compound (2.0 g,Yield 81%).

¹H-NMR (400 HMz, CDCl₃); δ 9.86 (br s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.14(d, J=8.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.61 (dd, J=0.8, 7.2 Hz, 1H),4.96 (m, 1H), 4.36 (m, 2H), 3.55 (m, 1H), 3.33 (m, 1H), 1.18 (s, 9H)

Preparation 32: Synthesis of 2,2-dimethyl-propionic acid(R)-2-(7-cyclopentyl amino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethylester

The compound obtained in Preparation 31 (2.0 g) was reacted according tothe same procedure as Example 1 to give the title compound (1.3 g, Yield54%).

Example 5 Synthesis of[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-methanol

[(R)-2-(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

The compound obtained in Preparation 32 (1.3 g, 3.3 mmol) was dissolvedin tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). Lithiumhydroxide hydrate (0.4 g, 9.8 mmol) was added. The mixture was stirredfor 4 h at room temperature, distilled under reduced pressure andconcentrated. 1N hydrochloric acid was added to the residue. The mixturewas extracted with ethyl acetate, dried over anhydrous magnesium sulfateand filtered. The filtrate was distilled under reduced pressure andpurified by column chromatography to give the title compound (820 mg,Yield 80%).

¹H-NMR (500 HMz, CDCl₃); δ 11.17˜11.08 (m, 1H), 7.09 (m, 1H), 6.99 (t,1H), 6.96 (s, 1H), 6.52 (m, 1H), 4.72 (m, 1H), 4.04 (m, 1H), 3.75 (m,1H), 3.65 (m, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 1.90 (m, 2H), 1.60˜1.49(m, 4H), 1.41˜1.24 (m, 2H)

Mass spectrum (ESI, m/z): Calculated: 315.14, Found: 315.44

Preparation 33: Synthesis of methanesulfonic acid(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethylester

The compound obtained in Example 5 (820 mg, 2.6 mmol) was dissolved indichloromethane (50 ml). Methanesulfonyl chloride (0.24 ml, 3.1 mmol)and triethylamine (0.81 ml, 3.1 mmol) were added, which was then stirredfor 30 min at 0□. After completion of the reaction, saturated sodiumbicarbonate solution was added. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled under reduced pressure and purified by columnchromatography to give the title compound (600 mg, Yield 60%).

Example 6 Synthesis ofcyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine

Cyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine

The compound obtained in Preparation 33 (150 mg, 0.38 mmol) wasdissolved in N,N-dimethylformamide (5 ml). Pyrrolidine (0.08 ml, 1.1mmol) was added, and stirred for 4 h at 70□. After completion of thereaction, water was added. The mixture was extracted with ethyl acetate,dried over anhydrous magnesium sulfate and filtered. The filtrate wasdistilled under reduced pressure and purified by column chromatographyto give the title compound (20 mg, Yield 14%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.37 (br s, 1H), 6.83 (m, 1H), 6.75 (d,J=2.0 Hz, 1H), 6.29 (d, J=8.0 Hz, 1H), 5.86 (d, J=8.0 Hz, 1H), 4.80 (m,1H), 3.87 (m, 1H), 3.52 (m, 1H), 3.43 (m, 1H), 3.33 (m, 2H), 2.78 (m,2H), 2.61 (m, 2H), 1.99 (m, 2H), 1.72 (m, 6H), 1.60 (m, 4H)

Example 7 Synthesis of{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

{(R)-2-[7-(Tetrahydro-pyran-4-ylami no)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

(Step 1)

The compound obtained in Preparation 31 (900 mg, 2.7 mmol) was dissolvedin 1,2-dichloroethane (100 ml). Tetrahydro-4H-pyran-4-one (0.8 ml, 8.13mmol), sodium triacetoxyborohydride (1.72 g, 8.13 mmol) and acetic acid(0.47 ml, 8.13 mmol) were added, and stirred for 48 h at roomtemperature. After completion of the reaction, the mixture was dilutedwith dichloromethane, washed with saturated sodium bicarbonate solution,dried over anhydrous magnesium sulfate and filtered. The filtrate wasdistilled under reduced pressure and purified by column chromatographyto give 2,2-dimethylpropionic acid(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethylester.

¹H-NMR (400 HMz, CDCl₃); δ 10.91 (br s, 1H), 7.01˜6.91 (m, 3H), 6.48 (d,J=7.2 Hz, 1H), 4.86 (m, 1H), 4.34 (m 2H), 4.00 (m, 2H), 3.61 (m, 1H),3.54 (m, 3H), 3.31 (m, 1H), 2.05 (m, 2H), 1.55 (m, 2H), 1.16 (s, 9H)

(Step 2)

The compound obtained in Step 1 was dissolved in methanol (32 ml),tetrahydrofuran (32 ml) and water (16 ml). 1N sodium hydroxide (7 ml)was added, and stirred for 4 h at room temperature. After completion ofthe reaction, the mixture was distilled under reduced pressure,extracted with dichloromethane, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled under reduced pressure and purified by columnchromatography to give the title compound (700 mg, Yield 78%).

¹H-NMR (500 HMz, CDCl₃); δ 11.04˜10.95 (m, 1H), 7.11 (m, 1H), 6.99 (t,1H), 6.96 (s, 1H), 6.52 (m, 1H), 4.74 (m, 1H), 4.02 (m, 1H), 3.92 (m,2H), 3.68 (m, 1H), 3.46˜3.30 (m, 5H), 1.91 (m, 2H), 1.28 (m, 2H)

Mass spectrum (ESI, m/z): Calculated: 331.14, Found: 331.44

Example 8 Synthesis of[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

[(R)-2-(7-Cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

Ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate obtained in Preparation 2(3.0 g, 11.9 mmol) was reacted according to the same procedure asExample 5 to give the title compound (600 mg, Yield 15%).

¹H-NMR (400 HMz, CDCl₃); δ 10.73 (br s, 1H), 6.91 (s, 1H), 6.72 (m, 1H),6.33 (m, 1H), 4.78 (m, 1H), 4.12 (m, 1H), 3.97 (br s, 1H), 3.79 (m, 1H),3.75 (m, 1H), 3.49 (m, 2H), 2.01 (m, 2H), 1.62 (m, 4H), 1.41 (m, 2H)

Example 9 Synthesis of{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

{(R)-2-[5-Fluoro-7-(tetrahydro-pyra n-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

Ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate obtained in Preparation 2(3.0 g, 11.9 mmol) was reacted according to the same procedure asExample 7 to give the title compound (750 mg, Yield 18%).

¹H-NMR (400 HMz, CDCl₃); δ 10.45 (br s, 1H), 6.90 (s, 1H), 6.75 (m, 1H),6.34 (m, 1H), 4.82 (m, 1H), 4.12 (m, 1H), 4.01 (m, 2H), 3.94 (m, 1H),3.78 (m, 1H), 3.54˜3.43 (m, 5H), 2.03 (m, 2H), 1.50 (m, 2H)

Example 10 Synthesis of{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

{(R)-2-[5-(Pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

7-Nitro-5-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid ethyl esterobtained in Preparation 11 (500 mg, 1.5 mmol) was reacted according tothe same procedure as Example 7 to give the title compound (40 mg, Yield6%).

¹H-NMR (400 HMz, CDCl₃); δ 10.96 (br s, 1H), 8.36 (d, J=2.4 Hz, 1H),8.26 (m, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 6.83 (s, 1H), 6.63 (d, J=1.6Hz, 1H), 6.24 (d, J=1.6 Hz, 1H), 4.81 (m, 1H), 4.01˜3.94 (m, 3H), 3.75(m, 1H), 3.47 (, 3H), 3.48˜3.29 (m, 5H), 1.93 (m, 2H), 1.52 (m, 2H)

Preparation 34: Synthesis of 5-chloro-7-nitro-1H-indole-2-carboxylicacid

The compound obtained in Preparation 5 (15.0 g, 59.1 mmol) was dissolvedin tetrahydrofuran (300 ml) and methanol (100 ml). Lithium hydroxide(7.43 g, 177 mmol) was dissolved in water (100 ml) and added to thereaction solution, which was then stirred for 3 h at room temperature.After completion of the reaction, tetrahydrofuran and methanol wereremoved by distillation under reduced pressure. The residue wasneutralized to about pH 6 using 3N hydrochloric acid solution. Theresulting solid was filtered and dried to give the title compound (13.1g, Yield 92%).

Preparation 35: Synthesis of[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

(Step 1)

The compound obtained in Preparation 34 (12.5 g, 52.0 mmol) and thecompound obtained in Preparation 22 (19.1 g, 62.4 mmol) were dissolvedin N,N-dimethylformamide (200 ml). Triethylamine (8.7 ml, 62.4 mmol),HOBT (14.0 g, 104 mmol) and EDC (16.9 g, 88.4 mmol) were added, andstirred for 4 h at room temperature. After completion of the reaction,the mixture was concentrated. The residue was extracted with ethylacetate and washed with saturated sodium hydrogen carbonate aqueoussolution and saturated ammonium chloride aqueous solution, respectively.The organic layer was concentrated, and the residue was purified bycolumn chromatography to give(R)-3-[(5-chloro-7-nitro-1H-indole-2-carbonyl)-amino]-4-(4-methoxy-benzylsulfanyl)-butyricacid methyl ester (20.2 g, 41.0 mmol, Yield 79%).

¹H-NMR (500 HMz, CDCl₃); δ 10.47 (br s, 1H), 8.24 (d, J=1.9 Hz, 1H),7.96 (d, J=1.9 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 6.89 (s, 1H), 6.81 (d,J=8.6 Hz, 2H), 4.58 (m, 1H), 3.75 (s, 3H), 3.73 (s, 2H), 3.71 (s, 3H),2.86 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.70 (m, 1H)

(Step 2)

The compound obtained in Step 1 was dissolved in dichloromethane (200ml). Phosphorus pentachloride (17.1 g, 82 mmlol) was added, and stirredfor 1 h at room temperature. After completion of the reaction, themixture was concentrated, and diethylether (200 ml) was added to theresidue. The resulting solid was filtered and dried to give[(R)-2-(5-chloro-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester.

¹H-NMR (500 HMz, CDCl₃); δ 10.48 (br s, 1H), 8.22 (d, J=1.8 Hz, 1H),7.94 (d, J=1.8 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 6.96 (d, J=2.5 Hz, 1H),6.89 (d, J=8.6 Hz, 2H), 5.00 (m, 1H), 3.76 (s, 3H), 3.71 (m, 1H), 3.26(m, 1H), 2.99 (m, 1H), 2.67 (m, 1H)

(Step 3)

The compound obtained in Step 2 was dissolved in tetrahydrofuran (200ml), methanol (200 ml) and water (200 ml). Iron dust (22.9 g, 410 mmol)and ammonium chloride (21.9 g, 410 mmol) were added, and stirred using amechanical stirrer for 1 h at 60□. After completion of the reaction,tetrahydrofuran (300 ml) was added. The mixture was filtered through acellite, washed with tetrahydrofuran (100 ml), distilled under reducedpressure and concentrated. The residue was extracted with ethyl acetate,washed with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate and filtered. The filtrate was distilled under reducedpressure and purified by column chromatography to give the titlecompound (9.0 g, Yield 68%).

Preparation 36: Synthesis of[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound obtained in Preparation 35 (4.9 g, 15.1 mmol) was dissolvedin dichloroethane (100 ml). Cyclopentanone (2.7 ml, 30.3 mmol), glacialacetic acid (0.86 ml, 15.1 mmol) and sodium triacetoxyborohydride (6.42g, 30.3 mmol) were added, which was then stirred for 36 h at roomtemperature. After completion of the reaction, the reaction mixture waswashed with saturated sodium hydrogen carbonate solution (200 ml) andconcentrated. The residue was purified by column chromatography to givethe title compound (5.15 g, Yield 87%).

¹H NMR (DMSO-d₆, ppm); δ 11.51 (s, 1H), 6.79 (s, 1H), 6.79 (s, 1H), 6.16(s, 1H), 6.13 (d, 1H), 4.85 (m, 1H), 3.80 (m, 1H), 3.62 (m, 1H), 3.58(s, 3H), 3.19 (m, 1H), 2.71 (m, 1H), 2.63 (m, 1H), 1.93 (m, 2H), 1.69(m, 2H), 1.56 (m, 4H)

FAB MS (m/e)=392

Example 11 Synthesis of[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

[(R)-2-(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound obtained in Preparation 36 (1.5 g, 3.83 mmol) was dissolvedin tetrahydrofuran (100 ml) and methanol (50 ml). Lithium hydroxidemonohydrate (640 mg, 15.3 mmol) was dissolved in water (50 ml) and addedto the reaction solution, which was then stirred for 4 h at roomtemperature. After completion of the reaction, tetrahydrofuran andmethanol were removed by distillation under reduced pressure. 1Nhydrochloric acid solution was added. The mixture was extracted withethyl acetate, washed with saturated sodium chloride solution, driedover anhydrous magnesium sulfate and filtered. The filtrate wasdistilled under reduced pressure and purified by column chromatographyto give the title compound (13.1 g, Yield 92%).

¹H NMR (DMSO-d₆, ppm); δ 12.51 (br s, 1H), 11.51 (s, 1H), 6.79 (s, 1H),6.79 (s, 1H), 6.16 (s, 1H), 6.14 (d, 1H), 4.87 (m, 1H), 3.80 (m, 1H),3.61 (m, 1H), 3.19 (m, 1H), 2.72 (m, 1H), 2.64 (m, 1H), 1.93 (m, 2H),1.69 (m, 2H), 1.56 (m, 4H)

FAB MS (m/e)=378

Example 12 Synthesis of[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester

[(R)-2-(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester

The compound obtained in Preparation 5 (5.0 g, 19.7 mmol) and thecompound obtained in Preparation 23 (6.3 g, 19.7 mmol) were reactedaccording to the same procedures as Preparations 34 to 36 to give thetitle compound (840 mg, Yield 11%).

Example 13 Synthesis of2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol

2-{(R)-2-[5-Chloro-7-(tetrahydro-py ran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol

(Step 1)

The compound obtained in Preparation 35 (4.0 g, 12.4 mmol) was reactedaccording to the same procedure as Step 1 of Example 7 to givetetrahydropyran-4-ylamine compound (4.1 g, 10.0 mmol, Yield; 81%).

¹H NMR (DMSO-d₆, ppm); δ 11.52 (1H, s), 6.81 (1H, s), 6.71 (1H, s), 6.28(1H, s), 6.07 (1H, d), 4.90 (1H, m), 3.86 (2H, m), 3.64 (3H, s), 3.62(2H, m), 3.44 (2H, t), 2.82-2.71 (2H, m), 1.94 (2H, m), 1.40 (2H, m)

FAB MS (m/e)=408

(Step 2)

The compound obtained in Step 1 (2.5 g, 6.12 mmol) was reacted accordingto the same procedure as Example 4 to give the title compound (2.19 g,5.76 mmol, Yield 94%).

¹H NMR (DMSO-d₆, ppm); δ 11.48 (br s, 1H), 6.81 (s, 1H), 6.68 (s, 1H),6.28 (s, 1H), 6.05 (d, 1H), 4.66 (q, 1H), 4.54 (t, 1H), 3.87 (m, 2H),3.61-3.54 (m, 3H), 3.44 (t, 2H), 3.15 (m, 1H), 1.99-1.93 (m, 3H), 1.73(m, 1H), 1.40 (m, 2H), 1.20 (m, 1H)

FAB MS (m/e)=380

Preparation 37: Synthesis of{5-chloro-2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound obtained in Example 13 (3.7 g, 10.2 mmol) was dissolved intetrahydrofuran (100 ml). Imidazole (2.1 g, 30.6 mmol),triphenylphosphine (4.0 g, 15.3 mmol) and iodine (3.9 g, 15.3 mmol) wereadded, and stirred for 8 h at 0□˜room temperature. After completion ofthe reaction, ethyl acetate (100 ml) was added, and the reaction mixturewas washed with water (100 ml×2). The organic layer was concentrated andthe residue was purified by column chromatography to give the titlecompound (2.0 g, 4.07 mmol, Yield 40%).

Example 14 Synthesis of1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone

1-[4-(2-{(R)-2-[5-Chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone

(Step 1)

The compound obtained in Preparation 37 (100 mg, 0.2 mmol) and1-t-butoxycarbonyl-piperazine (270 mg, 1.4 mmol) were dissolved inN,N-dimethylformamide (20 ml). Potassium carbonate (200 mg, 1.4 mmol)was added, and stirred for 4 h at room temperature. After completion ofthe reaction, water was added. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled under reduced pressure and concentrated to give4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazine-1-carboxylicacid t-butyl ester.

(Step 2)

The compound obtained and concentrated in Step 1 was dissolved indichloromethane (10 ml). 4N-hydrochloric acid solution (0.5 ml) wasadded in drops, and stirred for 2 h at room temperature. Aftercompletion of the reaction, the reaction mixture was concentrated bydistillation under reduced pressure. The concentrate was dissolved inN,N-dimethylformamide (5 ml). Glycolic acid (15.1 mg, 0.2 mmol),triethylamine (28 ul, 0.2 mmol), EDC (45 mg, 0.23 mmol) and HOBT (40 mg,0.29 mmol) were added, and stirred for 8 h at room temperature.1N-hydrochloric acid solution was added. The mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled under reduced pressure and purified by columnchromatography to give the title compound (5.1 mg, Yield 5%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 6.81 (s, 1H), 6.69 (d,J=1.8 Hz, 1H), 6.29 (s, 1H), 6.05 (d, J=7.4 Hz, 1H), 4.62 (m, 1H), 4.49(t, 1H), 4.04 (m, 2H), 3.87 (m, 2H), 3.56 (m, 1H), 3.45 (m, 4H), 3.29(m, 4H), 3.16 (m, 1H), 2.36 (m, 4H). 1.96 (m, 3H), 1.80 (m, 1H), 1.40(m, 2H)

Example 15 Synthesis of1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-ol

1-(2-{(R)-2-[5-Chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-ol

The compound obtained in Preparation 37 (100 mg, 0.2 mmol) and3-pyrrolidinol (0.35 ml, 4.2 mmol) were dissolved inN,N-dimethylformamide (20 ml). Potassium carbonate (580 mg, 4.2 mmol)was added and stirred for 4 h at room temperature. After completion ofthe reaction, water was added. The reaction mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was distilled under reduced pressure and concentrated. Theresidue was purified by column chromatography to give the title compound(2 mg, Yield 2%).

Example 16 Synthesis of[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

[(R)-2-(5-Bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]aceticacid

Methyl 5-bromo-7-nitro-1H-indole-2-carboxylate obtained in Preparation 6(1.1 g, 3.7 mmol) was reacted according to the same procedure as Example11 to give the title compound (250 mg, Yield 16%).

¹H-NMR (400 HMz, CDCl₃); δ 12.50 (br s, 1H), 7.10 (sm 1H), 7.06 (s, 1H),6.56 (s, 1H), 5.31 (m, 1H), 3.89 (m, 2H), 3.40 (m, 1H), 2.99 (m, 1H),2.83 (m, 1H), 2.08 (m, 2H), 1.86 (m, 2H), 1.66 (m, 4H)

Example 17 Synthesis of[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

[(R)-2-(7-Cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

Methyl 5-ethoxy-7-nitro-1H-indole-2-carboxylate obtained in Preparation9 (1.5 g, 5.7 mmol) was reacted according to the same procedure asExample 11 to give the title compound (150 mg, Yield 7%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.24 (br s, 1H), 6.65 (d, J=2.0 Hz, 1H),6.26 (d, J=2.0 Hz, 1H), 5.92 (d, J=6.0 Hz, 1H), 5.88 (d, J=2.0 Hz, 1H),4.89 (m, 1H), 3.94 (q, 2H), 3.81 (m, 1H), 3.65 (m, 1H), 3.20 (m, 1H),2.74 (m, 1H), 2.62 (m, 1H), 1.94 (m, 2H), 1.72 (m, 2H), 1.61 (m, 4H),1.31 (t, 3H)

Example 18 Synthesis of[(S)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

[(S)-2-(7-Cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

(Step 1)

D-Cysteine (5.0 g, 31.7 mmol) was used instead of L-cysteine in theprocedure of Preparation 22 to give(S)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric methyl ester (1.2 g,Yield 12%).

(Step 2)

5-Ethoxy-7-nitro-1H-indole-2-carboxylate obtained in Preparation 9 (1.0g, 3.8 mmol) and the compound obtained in Step 1 were reacted accordingto the same procedures as Preparation 34 to 36 and Example 11 to givethe title compound (27 mg, Yield 2%).

Example 19 Synthesis of[2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

[2-(7-Cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

(Step 1)

3-t-Butoxycarbonylamino-4-hydroxy-butyric acid ethyl ester (15.0 g, 60.7mmol) was used instead of(R)-4-t-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester in theprocedure of Preparation 24 to give3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid ethyl ester (12.0 g,Yield 61%).

(Step 2)

The compound of Step 1 and 7-nitro-5-phenoxy-1H-indole-2-carboxylic acidmethyl ester of Preparation 10 (2.0 g, 6.7 mmol) were reacted accordingto the same procedures as Preparation 34 to 36 and Example 11 to givethe title compound (500 mg, Yield 17%).

Example 20 Synthesis of[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

[(R)-2-(7-Cyclopentylamino-5-phenox y-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid

7-Nitro-5-phenoxy-1H-indole-2-carboxylic acid methyl ester ofPreparation 10 (101.5 g, 264.7 mmol) and(R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid ethyl esterhydrochloride of Preparation 23 were reacted according to the sameprocedures as Preparation 34 to 36 and Example 11 to give the titlecompound (51.0 g, Yield 44%).

¹H-NMR (400 HMz, CDCl₃); δ 11.92 (br s, 1H), 7.28 (m, 2H), 7.00 (m, 4H),6.56 (s, 1H), 6.22 (s, 1H), 5.34 (br s, 1H), 3.81 (br s, 1H), 3.70 (m,1H), 3.22 (d, J=12.0 Hz, 1H), 2.76˜2.62 (m, 2H), 1.96 (m, 2H), 1.73 (m,2H), 1.58 (m, 4H)

Example 21 Synthesis of[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazole-4-yl]-aceticacid

[(S)-2-(7-Cyclopentylamino-5-phenox y-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid

7-Nitro-5-phenoxy-1H-indole-2-carboxylic acid methyl ester ofPreparation 10 (55.5 g, 185.9 mmol) and(S)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid isopropyl ester ofPreparation 25 were reacted according to the same procedures asPreparation 34 to 36 and Example 11 to give the title compound (21.0 g,Yield 26%).

Preparation 38: Synthesis of3-[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

Acid compound obtained in Preparation 34 (2.0 g, 8.3 mmol) and(R)-4-amino-5-(4-methoxy-benzylsulfanyl)-pentanoic acid ethyl esterhydrochloride obtained in Preparation 24 (3.4 g, 10.2 mmol) were reactedaccording to the same procedures as Example 35 to give the titlecompound (0.76 g, Yield 26%).

¹H-NMR (400 HMz, CDCl₃); δ 10.00 (br s, 1H), 7.08 (s, 1H), 6.80 (s, 1H),6.57 (s, 1H), 4.71 (m, 1H), 4.07 (m, 2H), 3.88 (br s, 2H), 3.55 (m, 1H),3.11 (m, 1H), 2.50 (t, 2H), 2.05 (m, 2H), 1.22 (t, 3H)

Example 22 Synthesis of3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

3-[(R)-2-(5-Chloro-7-cyclopentylami no-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid ethyl ester

The compound obtained in Preparation 38 (760 mg, 2.1 mmol) was reactedaccording to the same procedures as Example 1 to give the title compound450 mg (Yield 51%).

Example 23 Synthesis of3-[(R)-2-(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

3-[(R)-2-(5-Chloro-7-cyclopentylami no-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]propionic acid

The ester compound obtained in Example 22 (500 mg, 1.2 mmol) was reactedaccording to the same procedures as Example 11 to give the titlecompound 400 mg (Yield 85%).

¹H-NMR (400 HMz, DMSO-d₆, Na salt); δ 11.69 (br s, 1H), 6.82 (d, J=4.0Hz, 1H), 6.68 (s, 1H), 6.27 (s, 1H), 6.18 (s, 1H), 4.63 (m, 1H), 3.83(m, 1H), 3.50 (m, 1H), 3.13 (m, 1H), 2.08˜1.96 (m, 6H), 1.72 (m, 2H),1.58 (m, 4H)

Preparation 39: Synthesis of 2-pyridin-2-yl-1H-indol-7-ylamine

The compound obtained in Preparation 14 (1.0 g, 4.2 mmol) was reactedaccording to the same procedures as Step 3 of Preparation 31 to give thetitle compound 800 mg (Yield 92%).

Example 24 Synthesis of cyclopentyl-(2-pyridin-2-yl-1H-indol-7-yl)-amine

Cyclopentyl-(2-pyridin-2-yl-1H-indo l-7-yl)-amine

The compound obtained in Preparation 39 (150 mg, 0.7 mmol) was reactedaccording to the same procedures as Example 1 to give the title compound55 mg (Yield 28%).

¹H-NMR (400 HMz, CDCl₃); δ 10.85 (br s, 1H), 8.48 (m, 1H), 7.87 (d,J=8.0 Hz, 1H), 7.74 (m, 1H), 7.12 (m, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.00(s, 1H), 6.98 (m, 1H), 6.43 (d, J=7.2 Hz, 1H), 3.81 (m, 1H), 1.89 (m,2H), 1.49 (m, 4H), 1.26 (m, 2H)

Preparation 40: Synthesis of 2-pyrazin-2-yl-1H-indol-7-ylamine

The compound obtained in Preparation 15 (500 mg, 2.1 mmol) was reactedaccording to the same procedures as Step 3 of Preparation 31 to give thetitle compound 430 mg (Yield 98%).

Example 25 Synthesis of Cyclopentyl-(2-pyrazin-2-yl-1H-indol-7-yl)amine

Cyclopentyl-(2-pyrazin-2-yl-1H-indo l-7-yl)-amine

The compound obtained in Preparation 40 (80 mg, 0.38 mmol) was reactedaccording to the same procedures as Example 1 to give the title compound33 mg (Yield 31%).

¹H-NMR (400 HMz, CDCl₃); δ 9.72 (br s, 1H), 9.08 (d, J=1.2 Hz, 1H), 8.41(m, 1H), 8.37 (m, 1H), 7.12 (m, 2H), 7.05 (m, 1H), 6.55 (d, J=7.6 Hz,1H), 3.94 (m, 1H), 2.04 (m, 2H), 1.70˜1.48 (m, 6H)

Example 26 Synthesis of(2-pyrazin-2-yl-1H-indol-7-yl)-(tetrahydropyran-4-yl) amine

(2-Pyrazin-2-yl-1H-indol-7-yl)-(tet rahydro-pyran-4-yl)-amine

The compound obtained in Preparation 40 (80 mg, 0.38 mmol) was reactedaccording to the same procedures as Step 1 of Example 7 to give thetitle compound 35 mg (Yield 31%).

¹H-NMR (400 HMz, CDCl₃ & MeOH-d₄) δ 9.00 (br s, 1H), 8.51 (m, 1H), 8.35(d, J=2.4 Hz, 1H), 7.13 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.00 (m, 1H),6.52 (d, J=7.6 Hz, 1H), 4.05 (m, 2H), 3.68 (m, 1H), 3.61 (m, 2H), 2.17(m, 2H), 1.63 (m, 2H)

Preparation 41: Synthesis of 7-nitro-1H-indol-2-carbothioic acid amide

7-Nitroindol-2-carboxylic acid compound obtained in Step 1 ofPreparation 28 (2.0 g, 9.7 mmol) was dissolved in dichloromethane (100ml). 2 ml (29.1 mmol) of cyonylchloride was added and the mixture wasstirred for 1 hour at 60° C. At the end of reaction, the mixture wasdistilled under reduced pressure to concentrate. The resulting compoundwas dissolved in 100 ml of tetrahydrofuran and 5.0 g (14.6 mmol) ofLawesson's reagent was added. The mixture was stirred for 3 hours at 80°C. At the end of reaction, the mixture was concentrated. The resultingsolids were washed with 100 ml of chloromethane to give the titlecompound 1.5 g (Yield 71%).

¹H-NMR (500 HMz, DMSO-d₆); δ 10.92 (br s, 1H), 10.00 (br s, 1H), 9.99(br s, 1H), 8.22 (m, 2H), 7.50 (d, J=1.9 Hz, 1H), 7.30 (t, 1H)

Preparation 42: Synthesis of 7-nitro-2-thiazol-2-yl-1H-indole

1.1 g (5.0 mmol) of the compound obtained in Preparation 41 wasdissolved in 20 ml of ethanol and 1 ml of N,N-dimethylformamide 3.7 ml(25 mmol) of Bromoacetaldehyde diethylacetal was added and the mixturewas stirred for 8 hours at 100° C. At the end of reaction, added waterand extracted with ethylacetate. The extract was dried over anhydrousmagnesium sulfate and filtered. The filtrate was distilled under reducedpressure to concentrate. The resulting solids were washed with diethylether to give the title compound 800 mg (Yield 67%).

Preparation 43: Synthesis of 2-thiazol-2-yl-1H-indol-7-ylamine

The compound obtained in Preparation 42 (800 mg, 3.3 mmol) was reactedaccording to the same procedures as Step 3 of Preparation 31 to give thetitle compound 650 mg (Yield 93%).

¹H-NMR (500 HMz, DMSO-d₆); δ 10.79 (br s, 1H), 9.43 (br s, 1H), 9.29 (brs, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.77˜6.71 (m, 2H), 6.33 (m, 1H), 5.50(br s, 2H)

Example 27 Synthesis of Cyclopentyl-(2-thiazol-2-yl-1H-indol-7-yl)-amine

Cyclopentyl-(2-thiazol-2-yl-1H-indo l-7-yl)-amine

The compound obtained in Preparation 43 (30 mg, 3.3 mmol) was reactedaccording to the same procedures as Example 1 to give the title compound20 mg (Yield 51%).

¹H-NMR (400 HMz, CDCl₃); δ 9.37 (br s, 1H), 7.36 (br s, 1H), 7.20 (br s,1H), 7.06˜7.00 (m, 2H), 6.86 (d, J=2.0 Hz, 1H), 6.55 (m, 2H), 3.95 (m,1H), 2.08 (m, 2H), 1.79 (m, 2H), 1.65 (m, 4H)

Preparation 44: Synthesis of 5-methyl-7-nitro-1H-indol-2-carboxylic acid

6.5 g (27.8 mmol) of the compound obtained from Preparation 7 wasdissolved in 200 ml of 1:1:1 mixture solution of methanol,tetrahydrofuran and water. 3.5 g (83.3 mmol) of Lithium hydroxidehydrate was added thereto. After stirring for 8 hours at roomtemperature, 1N—HCl solution was added and the mixture was extractedwith ethylacetate. The extract was dried over anhydrous magnesiumsulfate and filtered. The filtrate was distilled under reduced pressureto obtain the title compound 5.7 g (Yield 94%).

¹H-NMR (500 HMz, CDCl₃); δ 10.26 (br s, 1H), 8.17 (s, 1H), 7.87 (s, 1H),7.38 (s, 1H), 2.59 (s, 3H)

Preparation 45: Synthesis of(R)-3-(4-methoxy-benzylsulfanyl)-2-[(5-methyl-7-nitro-1H-indol-2-carbonyl)-amino]-propionicacid ethyl ester

The compound obtained in Preparation 44 (3 g, 13.6 mmol) and(R)-2-amino-3-(4-methoxy-benzylsulfanyl) propionic acid ethyl esterhydrochloride obtained in Preparation 26 (5.8 g, 19.1 mmol) wasdissolved in 100 ml of dimethylformamide. Triethylamine (1.9 g, 19.1mmol), EDC (4.4 g, 23.2 mmol) and HOBT (3.7 g, 27.3 mmol) were addedthereto. After stirring for 8 hours at room temperature, 1N—HCl solutionwas added and the mixture was extracted with ethylacetate. The extractwas dried over anhydrous magnesium sulfate and filtered. The filtratewas distilled under reduced pressure and purified by columnchromatography to obtain the title compound 4.1 g (Yield 64%).

¹H-NMR (400 HMz, CDCl₃); δ 10.06 (br s, 1H), 7.95 (s, 1H), 7.64 (s, 1H),7.51 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.87 (s, 1H), 6.86 (d,J=4.0 Hz, 2H), 5.05 (m, 1H), 4.30 (m, 2H), 3.72 (s, 5H), 3.04 (m, 2H),2.44 (s, 3H), 1.30 (t, 3H)

Preparation 46: Synthesis of(R)-2-(7-amino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazole-4-carboxylicacid ethyl ester

(Step 1)

The compound obtained in Preparation 45 (4.1 g, 8.7 mmol) of wasdissolved in 200 ml of dichloromethane, thereto 3.6 g (17.4 mmol) ofPhosphorus pentachloride was added. The mixture was stirred for 4 hoursat room temperature. Saturated aqueous sodium bicarbonate solution wasadded, and the mixture was extracted with ethylacetate. The extract wasdried with anhydrous magnesium sulfate, filtered. The filtrate wasdistilled under reduced pressure to give(R)-2-(5-methyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-carboxylicacid ethyl ester.

(Step 2)

The compound obtained in Step 1 was dissolved in 300 ml of 1:1:1 mixtureof water, tetrahydrofuran and methanol. To the mixture added 4.6 g (86.9mmol) of ammonium chloride and 4.9 g (86.9 mmol) of iron and stirred for30 minutes at 60° C. The mixture was filtered through celite anddistilled under reduced pressure. To the concentrate added saturatedaqueous sodium bicarbonate solution and extracted with ethylacetate. Theextract was dried with anhydrous magnesium sulfate, filtered. Thefiltrate was purified by column chromatography to give the titlecompound 400 mg (Yield 15%).

Preparation 47: Synthesis of(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thizole-4-carboxylicacid ethyl ester

The compound obtained in Preparation 46 (4.0 g, 0.91 mmol) was reactedaccording to the same procedures as Example 1 to give the title compound590 mg (Yield 12%).

¹H-NMR (400 HMz, CDCl₃); δ 9.74 (br s, 1H), 6.85 (s, 1H), 6.84 (s, 1H),6.37 (s, 1H), 5.32 (t, 1H), 4.24 (m, 2H), 3.88 (m, 1H), 3.71 (m, 2H),2.39 (s, 3H), 2.03 (m, 2H), 1.67 (m, 2H), 1.61 (m, 2H), 1.47 (m, 2H)

Example 28 Synthesis of2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-thizole-4-carboxylic acidethyl ester

2-(7-Cyclopentylamino-5-methyl-1H-i ndol-2-yl)-thiazole-4-carboxylic acid ethyl ester

The compound obtained in Preparation 47 (560 mg, 1.51 mmol) wasdissolved in 20 ml of dichloromethane. Bromotrichloromethane (330 mg,1.7 mmol) and DBU (250 mg, 1.7 mmol) were added. The mixture was stirredfor 2 hours at 0° C. At the end of reaction, added saturated aqueoussodium bicarbonate solution and extracted with ethylacetate. The extractwas dried with anhydrous magnesium sulfate, filtered. The filtrate wasdistilled under reduced pressure and purified by column chromatographyto give the title compound 450 mg (Yield 81%).

¹H-NMR (400 HMz, CDCl₃); δ 9.36 (br s, 1H), 8.07 (s, 1H), 6.91 (d, J=4.0Hz, 1H), 6.84 (s, 1H), 6.37 (s, 1H), 4.37 (q. 2H), 3.95 (m, 1H), 2.40(s, 3H), 2.03 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H), 1.55 (m, 2H), 1.33(t, 3H)

Example 29 Synthesis of2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-thizole-4-carboxylic acid

2-(7-Cyclopentylamino-5-methyl-1H-i ndol-2-yl)-thiazole-4-carboxylic acid

The compound obtained in Example 28 (100 mg, 0.27 mmol) was reactedaccording to the same procedures as Preparation 44 to give the titlecompound 70 mg (Yield 76%).

¹H-NMR (400 HMz, DMSO-d₆, Na salt); δ 13.20 (br s, 1H), 7.89 (s, 1H),6.81 (s, 1H), 6.65 (br s, 1H), 6.59 (s, 1H), 6.13 (s, 1H), 3.87 (m, 1H),2.31 (s, 3H), 2.01 (m, 2H), 1.75 (m, 4H), 1.55 (m, 2H)

Example 30 Synthesis of[2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-thizole-4-yl]-methanol

[2-(7-Cyclopentylamino-5-methyl-1H-indol-2-yl)-thiazol-4-yl]-methanol

The compound obtained in Example 28 (300 mg, 0.81 mmol) was reactedaccording to the same procedures as Example 4 to give the title compound200 mg (Yield 75%).

¹H-NMR (400 HMz, CDCl₃); δ 10.42 (br s, 1H), 7.14 (s, 1H), 6.88 (d,J=4.0 Hz, 1H), 6.86 (s, 1H), 4.70 (s, 2H), 3.81 (m, 1H), 2.39 (s, 3H),1.96 (m, 2H), 1.61 (m, 4H), 1.36 (m, 2H)

Preparation 48: Synthesis of 5-methyl-7-nitro-1H-indole-2-carbothioicacid amido

The carboxylic acid compound obtained in Preparation 44 (3.2 g, 1.4mmol) was reacted according to the same procedures as Preparation 41 togive the title compound 2.4 g (Yield 75%).

¹H-NMR (400 HMz, DMSO-d₆); δ 10.83 (br s, 1H), 10.00 (br s, 1H), 9.87(br s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.45 (s, 1H), 2.50 (s, 3H)

Preparation 49: Synthesis of2-(5-methyl-7-nitro-1H-indol-2-yl)-thiazole-5-carbaldehyde

The compound obtained in Preparation 48 (2.5 g, 11.3 mmol) was dissolvedin 50 ml of N, N-dimethylformamide. To the solution added 2.56 g (17mmol) of 2-bromo malonaldehyde and stirred for 6 hours at 100° C. At theend of reaction, the reaction mixture was added to ice water. Theresulting solids were collected and dried to give the title compound2.45 g (Yield 77%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.70 (br s, 1H), 10.11 (s, 1H), 8.82 (s,1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.56 (s, 1H), 2.50 (s, 3H)

Preparation 50: Synthesis of[2-(7-amino-5-methyl-1H-indol-2-yl)-thiazol-5-yl]-methanol

The compound obtained in Preparation 49 (1.75 g, 6.1 mmol) was dissolvedin 300 ml of 1:1:1 mixture of water, tetrahydrofuran and methanol. Tothe mixture added 3.26 g (60.9 mmol) of ammonium chloride and 3.4 g(60.9 mmol) of iron and stirred for 30 minutes at 60° C. The mixture wasfiltered through celite and distilled under reduced pressure. To theconcentrate added saturated aqueous sodium bicarbonate solution andextracted with ethylacetate. The extract was dried with anhydrousmagnesium sulfate, filtered. The filtrate was distilled under reducedpressure and purified by column chromatography to give the titlecompound 300 mg (Yield 19%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.27 (br s, 1H), 7.69 (s, 1H), 6.76 (d,J=4.0 Hz, 1H), 6.20 (s, 1H), 5.60 (t, 1H), 5.26 (br s, 2H), 4.71 (d,J=8.0 Hz, 2H), 2.23 (s, 3H)

Example 31 Synthesis of[2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-thiazol-5-yl]-methanol

[2-(7-Cyclopentylamino-5-methyl-1H-indol-2-yl)-thiazol-5-yl]-methanol

The compound obtained in Preparation 50 (300 mg, 1.16 mmol) was reactedaccording to the same procedures as Example 1 to give the title compound380 mg (Yield 100%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.39 (br s, 1H), 7.70 (s, 1H), 6.78 (d,J=4.0 Hz, 1H), 6.60 (s, 1H), 6.11 (s, 1H), 5.72 (d, J=8.0 Hz, 1H), 5.62(t, 1H), 4.72 (d, J=4.0 Hz, 2H), 3.88 (m, 1H), 2.30 (s, 3H), 2.00 (m,2H), 1.74 (m, 2H), 1.60 (m, 4H)

Preparation 51: Synthesis of 5-methyl-7-nitro-1H-indol-2-carboxylic acidhydrazide

The compound obtained in Preparation 7 (5.0 g, 21.3 mmol) of wasdissolved in 100 ml of ethanol. 2 ml (40 mmol) of Hydrazine hydrate wasadded thereto, and the mixture was stirred for 4 hours at 100□. At theend of reaction, cooled the solution and solids were precipitated. Thesolids were collected and washed with dichloromethane to yield the titlecompound 2.34 g (Yield 47%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.08 (br s, 1H), 10.21 (br s, 1H), 8.05(s, 1H), 7.98 (s, 1H), 7.27 (s, 1H), 4.62 (br s, 2H), 2.48 (s, 3H)

Preparation 52: Synthesis of5-methyl-7-nitro-2-[1,3,4]oxadiazol-2-yl-1H-indole

2.3 g (9.8 mmol) of the compound obtained in Preparation 51 was combinedwith 100 ml of triethyl orthoformate and the mixture was stirred for 8hours at 120° C. At the end of reaction, added water and extracted withethylacetate. The extract was dried over anhydrous magnesium sulfate,filtered. The filtrate was distilled under reduced pressure to obtainthe title compound 600 mg (Yield 25%).

¹H-NMR (400 HMz, DMSO-d₆); δ 12.12 (br s, 1H), 9.46 (s, 1H), 8.11 (s,1H), 8.02 (s, 1H), 7.45 (s, 1H), 3.32 (s, 3H)

Example 32 Synthesis ofcyclopentyl-(5-methyl-2-[1,3,4]oxadiazol-2-yl-1H-indol-7-yl)-amine

Cyclopentyl-(5-methyl-2-[1,3,4]oxad iazol-2-yl-1H-indol-7-yl)-amine

The compound obtained in Preparation 52 (300 mg, 1.2 mmol) was reactedaccording to the same procedures as Preparation 43 and Example 1 to givethe title compound 50 mg (Yield 14%).

¹H-NMR (400 HMz, CDCl₃); δ 9.97 (br s, 1H), 8.43 (s, 1H), 7.10 (d, J=40Hz, 1H), 6.90 (s, 1H), 6.44 (s, 1H), 4.14 (m, 1H), 3.97 (m, 1H), 2.42(s, 3H), 2.08 (m, 2H), 1.74 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H)

Preparation 53: Synthesis of 5-methyl-2-pyridin-2-yl-1H-indol-7-ylamine

The compound obtained in Preparation 12 (300 mg, 1.2 mmol) of wasdissolved in 100 ml of 1:1 mixture of methanol and ethylacetate. 10%Pd/C 40 mg was added, and the mixture was stirred for 1 hour under thestream of hydrogen gas. At the end of reaction, the mixture was filteredthrough celite, and distilled under pressure. The distillate wasseparated by column chromatography to give the title compound 170 mg(Yield 64%).

¹H-NMR (400 HMz, CDCl₃); δ 9.67 (br s, 1H), 8.52 (m, 1H), 7.75 (m, 1H),7.69 (m, 1H), 7.13 (m, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.89 (d, J=2.4 Hz,1H), 6.60 (d, J=2.0 Hz, 1H), 6.27 (d, J=2.0 Hz, 1H), 4.04 (m, 2H), 1.40(m, 3H)

Example 33 Synthesis ofcyclopentyl-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amine

Cyclopentyl-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amine

The compound obtained in Preparation 53 (50 mg, 0.22 mmol) was reactedaccording to the same procedures as Example 1 to give the title compound20 mg (Yield 46%).

¹H-NMR (400 HMz, CDCl₃); δ 9.73 (br s, 1H), 8.53 (d, J=4.8 Hz, 1H), 7.78(d, J=8.0 Hz, 1H), 7.70 (m, 1H), 7.13 (m, 1H), 6.91 (d, J=2.0 Hz, 1H),6.87 (s, 1H), 6.32 (s, 1H), 3.91 (m, 1H), 3.60 (br s, 1H), 2.41 (s, 3H),2.00 (m, 2H), 1.65 (m, 4H), 1.51 (m, 2H)

Example 34 Synthesis of(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

(5-Methyl-2-pyridin-2-yl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

The compound obtained in Preparation 53 (50 mg, 0.22 mmol) was reactedaccording to the same procedures as Step 1 of Example 7 to give thetitle compound 25 mg (Yield 36%).

¹H-NMR (400 HMz, CDCl₃); δ 10.65 (br s, 1H), 8.49 (d, J=4.8 Hz, 1H),7.81 (d, J=8.0 Hz, 1H) 7.72 (m, 1H), 7.13 (m, 1H), 6.92 (d, J=2.0 Hz,1H), 6.88 (s, 1H), 6.27 (s, 1H), 3.92 (m, 1H), 3.49 (m, 3H), 2.39 (s,3H), 1.95 (m, 2H), 1.30 (m, 2H)

Example 35 Synthesis ofcyclohexyl-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amine

Cyclohexyl-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amine

The compound obtained in Preparation 53 (50 mg, 0.22 mmol) was reactedto give the title compound 25 mg (Yield 36%), according to the sameprocedures as Example 1 except that cyclohexanone was used instead ofcyclopentanone.

¹H-NMR (500 HMz, CDCl₃); δ 10.46 (br s, 1H), 8.48 (d, J=4.9 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 7.70 (m, 1H), 7.11 (m, 1H), 6.92 (d, J=1.8 Hz,1H), 6.85 (s, 1H), 3.30 (m, 1H), 2.39 (s, 3H), 1.98 (m, 2H), 1.70 (m,2H), 1.60 (m, 1H), 1.31 (m, 2H), 1.39 (m, 1H), 0.95 (m, 1H)

Example 36 Synthesis of1-[4-(5-methyl-2-pyridin-2-yl-1H-indol-7-ylamino)-piperidin-1-yl]-ethanone

1-[4-(5-Methyl-2-pyridin-2-yl-1H-in dol-7-ylamino)-piperidin-1-yl]-ethanone

The compound obtained in Preparation 53 (30 mg, 0.13 mmol) was reactedto give the title compound 10 mg (Yield 21%), according to the sameprocedures as Example 1 except that 1-acetyl-4-piperidone was usedinstead of cyclopentanone.

¹H-NMR (500 HMz, CDCl₃ & MeOH-d₄) δ 8.42 (d, J=4.9 Hz, 1H), 7.71 (d,J=8.0 Hz, 1H), 7.65 (m, 1H), 7.08 (m, 1H), 6.83 (s, 1H), 6.78 (s, 1H),6.22 (s, 1H), 4.33 (m, 1H), 3.77 (m, 1H), 3.60 (m, 1H), 3.52 (s, 3H),3.17 (m, 1H), 2.91 (m, 1H), 2.31 (s, 3H), 2.13 (m, 1H), 2.06 (m, 1H),1.39 (m, 2H)

Example 37 Synthesis of(1-methyl-piperidin-4-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amine

(1-Methyl-piperidin-4-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amin e

The compound obtained in Preparation 53 (30 mg, 0.13 mmol) was reactedto give the title compound 17 mg (Yield 40%), according to the sameprocedures as Example 1 except that 1-methyl-4-piperidone was usedinstead of cyclopentanone.

¹H-NMR (400 HMz, CDCl₃); δ 10.75 (br s, 1H), 8.45 (d, J=4.8 Hz, 1H),7.77 (d, J=8.0 Hz, 1H), 7.68 (m, 1H), 7.08 (m, 1H), 6.90 (d, J=2.0 Hz,1H), 6.85 (s, 1H), 6.24 (s, 1H), 3.30 (m, 1H), 2.73 (m, 2H), 2.38 (s,3H), 2.24 (s, 3H), 2.08 (m, 2H), 1.97 (m, 2H), 1.33 (m, 2H)

Example 38 Synthesis of4-(5-methyl-2-pyridin-2-yl-1H-indol-7-ylamino)-cyclohexanone

4-(5-Methyl-2-pyridin-2-yl-1H-indol-7-ylamino)-cyclohexanone

In 10 ml of acetone and 5 ml of water was dissolved the compoundobtained by reacting 30 mg (0.13 mmol) of the compound obtained inPreparation 53, according to the same procedures as Example 1 exceptthat 1,4-cyclohexanedione monoethylene acetal was used instead ofcyclopentanone. To the solution added 1 ml of 1 N hydrochloridesolution, and stirred for 8 hours at 80° C. At the end of reaction,added saturated sodium bicarbonate solution and extracted withethylacetate. The extract was dried with anhydrous magnesium sulfate,filtered, and distilled under reduced pressure. The distillate waspurified by column chromatography to give the title compound 10 mg(Yield 23%).

¹H-NMR (400 HMz, CDCl₃); δ 10.72 (br s, 1H), 8.48 (d, J=4.4 Hz, 1H),7.81 (d, J=8.0 Hz, 1H), 7.73 (m, 1H), 7.13 (m, 1H), 6.92 (d, J=2.0 Hz,1H), 6.91 (s, 1H), 6.32 (s, 1H), 3.78 (m, 1H) 2.41 (s, 3H), 2.35 (m,4H), 2.20 (m, 2H), 1.52 (m, 2H)

Example 39 Synthesis of(1-benzyl-pyrrolidin-3-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amine

(1-Benzyl-pyrrolidin-3-yl)-(5-methy l-2-pyridin-2-yl-1H-indol-7-yl)-amine

The compound obtained in Preparation 53 (30 mg, 0.13 mmol) was reactedto give the title compound 10 mg (Yield 20%), according to the sameprocedures as Example 1 except that 1-benzyl-3-pyrrolidone was usedinstead of cyclopentanone.

¹H-NMR (400 HMz, CDCl₃); δ 10.72 (br s, 1H), 8.49 (m, 1H), 7.76 (d,J=8.0 Hz, 1H), 7.66 (m, 1H), 7.31˜7.21 (m, 5H), 7.08 (m. 1H), 6.89 (d,J=2.0 Hz, 1H), 6.83 (s, 1H), 6.22 (s, 1H), 4.09 (br s, 1H), 3.61 (m,2H), 2.79 (m, 1H), 2.64 (m, 1H), 2.44 (m, 2H), 2.38 (s, 3H), 2.25 (m,1H), 1.61 (m, 1H)

Example 40 Synthesis ofcyclopentylmethyl-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-amine

Cyclopentylmethyl-(5-methyl-2-pyrid in-2-yl-1H-indol-7-yl)-amine

The compound obtained in Preparation 53 (30 mg, 0.13 mmol) was reactedto give the title compound 10 mg (Yield 20%), according to the sameprocedures as Example 1 except that cyclopentanecarboxaldehyde was usedinstead of cyclopentanone.

¹H-NMR (500 HMz, CDCl₃); δ 10.54 (br s, 1H), 8.48 (m, 1H), 7.79 (d,J=8.0 Hz, 1H), 7.71 (m, 1H), 7.12 (m, 1H), 6.93 (d, J=2.5 Hz, 1H), 6.88(s, 1H), 6.28 (s, 1H), 3.07 (d, J=7.3 Hz, 1H), 2.41 (s, 3H), 2.05 (m,1H), 1.69˜1.51 (m, 6H), 1.19 (m, 2H)

Example 41 Synthesis ofN-(5-methyl-2-pyridin-2-yl-1H-indole-7-yl)-benzamide

N-(5-Methyl-2-pyridin-2-yl-1H-indol-7-yl)-benzamide

The compound obtained in Preparation 53 (45 mg, 0.20 mmol) was dissolvedin chloromethane 10 ml. 0.2 ml of Triethylamine and 0.03 ml (0.22 mmol)of benzoylchloride were added and the mixture was stirred at roomtemperature for 2 hours. At the end of reaction, added water andextracted with ethylacetate. The extract was dried over anhydrousmagnesium sulfate, filtered. The filtrate was distilled under reducedpressure and purified by column chromatography to obtain the titlecompound 18 mg (Yield 27%).

¹H-NMR (500 HMz, CDCl₃); δ 10.98 (br s, 1H), 8.61 (s, 1H), 8.50 (d,J=4.9 Hz, 1H), 7.90 (d, J=7.4 Hz, 2H), 7.77 (d, J=8.0 Hz, 1H), 7.69 (m,1H), 7.50 (m, 1H), 7.43 (m, 2H), 7.31 (s, 1H), 7.26 (s, 1H), 7.14 (m,1H), 6.95 (d, J=1.8 Hz, 1H), 2.41 (s, 3H)

Example 42 Synthesis ofcyclopentyl-(5-methyl-2-pyrazin-2-yl-1H-indol-7-yl)amine

Cyclopentyl-(5-methyl-2-pyrazin-2-y l-1H-indol-7-yl)-amine

The compound obtained in Preparation 13 (100 mg, 0.39 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 to givethe title compound 25 mg (Yield 22%).

¹H-NMR (400 HMz, CDCl₃); δ 9.55 (br s, 1H), 9.06 (s, 1H), 8.41 (d, J=4.0Hz, 1H), 8.26 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 6.38 (s, 1H), 3.95(m, 1H), 2.41 (s, 3H), 2.06 (m, 2H), 1.71˜1.49 (m, 6H)

Example 43 Synthesis ofcyclopentyl-(5-ethoxy-2-pyridin-2-yl-1H-indol-7-yl)-amine

Cyclopentyl-(5-ethoxy-2-pyridin-2-y l-1H-indol-7-yl-amine

The compound obtained in Preparation 16 (20 mg, 0.07 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 to givethe title compound 4.5 mg (Yield 19%).

¹H-NMR (400 HMz, CDCl₃); δ 9.86 (br s, 1H), 8.56 (d, J=4.8 Hz, 1H), 7.81(d, J=8.0 Hz, 1H), 7.74 (m, 1H), 7.17 (m, 1H), 6.94 (d, J=2.0 Hz, 1H),6.54 (d, J=2.0 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H), 4.11 (q, 2H), 3.91 (m,1H), 2.05 (m, 2H), 1.76˜1.63 (m, 4H), 1.54˜1.46 (m, 5H)

Example 44 Synthesis ofcyclopentyl-(5-phenoxy-2-pyridin-2-yl-1H-indole-7-yl)-amine

Cyclopentyl-(5-phenoxy-2-pyridin-2-yl-1H-indol-7-yl)-amine

The compound obtained in Preparation 17 (250 mg, 0.75 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 to givethe title compound 120 mg (Yield 43%).

¹H-NMR (400 HMz, CDCl₃); δ 10.07 (br s, 1H), 8.55 (d, J=4.0 Hz, 1H),7.74 (m, 2H), 7.29 (m, 2H), 7.18 (m, 1H), 7.01 (m, 3H), 6.93 (d, J=4.0Hz, 1H), 6.69 (d, J=4.0 Hz, 1H), 6.27 (s, 1H), 3.81 (m, 1H), 3.70 (br s,1H), 1.96 (m, 2H), 1.60 (m, 4H), 1.41 (m, 2H)

Example 45 Synthesis ofcyclopentyl-(3,5-dimethyl-2-phenyl-1H-indole-7-yl)-amine

Cyclopentyl-(3,5-dimethyl-2-phenyl-1H-indol-7-yl)-amine

The compound obtained in Preparation 18 (100 mg, 0.38 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 to givethe title compound 35 mg (Yield 31%).

¹H-NMR (400 HMz, CDCl₃); δ 7.68 (br s, 1H), 7.59 (m, 2H), 7.45 (m, 2H),7.32 (m, 1H), 6.87 (s, 1H), 6.40 (s, 1H), 3.97 (m, 1H), 2.45 (s, 3H),2.40 (s, 3H), 2.09 (m, 2H), 1.78˜1.56 (m, 4H)

Example 46 Synthesis ofcyclopentyl-(5-methyl-2-phenyl-1H-indol-7-yl)-amine

Cyclopentyl-(5-methyl-2-phenyl-1H-i ndol-7-yl)-amine

The compound obtained in Preparation 19 (120 mg, 0.48 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 to givethe title compound 50 mg (Yield 36%).

¹H-NMR (500 HMz, MeOH-d₄) δ 7.74 (m, 2H), 7.38 (m, 2H), 7.24 (m, 1H),6.68 (s, 1H), 6.62 (s, 1H), 6.23 (s, 1H), 3.95 (m, 1H), 2.06 (m, 2H),1.80 (m, 2H), 1.65 (m, 4H)

Example 47 Synthesis of(2-cyclohexyl-5-methyl-1H-indol-7-yl)-cyclopentyl-amine

(2-Cyclohexyl-5-methyl-1H-indol-7-y l)-cyclopentyl-amine

The compound obtained in Preparation 20 (50 mg, 0.19 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 to givethe title compound 21 mg (Yield 37%).

¹H-NMR (400 HMz, CDCl₃); δ 7.80 (br s, 1H), 6.81 (s, 1H), 6.31 (s, 1H),6.08 (s, 1H), 3.93 (m, 1H), 2.92 (m, 1H), 2.38 (s, 3H), 2.08 (m, 4H),1.80˜1.20 (m, 14H)

Example 48 Synthesis ofcyclopentyl-[5-methyl-2-(6-methyl-pyridin-2-yl)-1H-indol-7-yl]-amine

Cyclopentyl-[5-methyl-2-(6-methyl-p yridin-2-yl)-1H-indol-7-yl]-amine

The compound obtained in Preparation 21 (50 mg, 0.19 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 to givethe title compound 35 mg (Yield 40%).

¹H-NMR (400 HMz, CDCl₃); δ 11.11 (br s, 1H) 7.59 (m, 2H), 6.94 (m, 1H),6.88 (d, J=2.0 Hz, 1H), 6.82 (s, 1H), 6.19 (s, 1H), 3.73 (m, 1H), 2.37(s, 3H), 2.31 (s, 3H), 1.80 (m, 2H), 1.43 (m, 4H), 1.14 (m, 2H)

Example 49 Synthesis of(5-methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

(5-Methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

The compound obtained in Preparation 19 (70 mg, 0.28 mmol) was reactedto give the title compound 50 mg (Yield 57%), according to the sameprocedures as Preparation 53 and Example 1 except thattetrahydro-4H-pyran-4-one was used instead of cyclopentanone.

¹H-NMR (500 HMz, MeOH-d₄); δ 7.74 (m, 2H), 7.39 (m, 2H), 7.24 (m, 1H),6.71 (s, 1H), 6.63 (s, 1H), 6.28 (s, 1H), 4.01 (m, 1H), 3.68 (m, 1H),3.58 (m, 2H), 2.32 (s, 3H), 2.12 (m, 2H), 1.56 (m, 2H)

Example 50 Synthesis of(5-methyl-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl)-amine

(5-Methyl-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl)-amine

The compound obtained in Preparation 19 (70 mg, 0.28 mmol) was reactedto give the title compound 24 mg (Yield 29%), according to the sameprocedures as Preparation 53 and Example 1 except that1-methyl-4-piperidone was used instead of cyclopentanone.

¹H-NMR (500 HMz, MeOH-d₄); δ 7.73 (m, 2H), 7.38 (m, 2H), 7.24 (m, 1H),6.70 (s, 1H), 6.63 (s, 1H), 6.24 (s, 1H), 3.47 (m, 1H), 2.96 (m, 2H),2.34 (s, 3H), 2.32 (s, 3H), 2.26 (m, 2H), 2.17 (m, 2H), 1.59 (m, 2H)

Example 51 Synthesis of1-[4-(5-methyl-2-phenyl-1H-indol-7-ylamino)-piperidin-1-yl]-ethanone

1-[4-(5-Methyl-2-phenyl-1H-indol-7-ylamino)-piperidin-1-yl]-ethanone

The compound obtained in Preparation 19 (96 mg, 0.38 mmol) was reactedto give the title compound 18 mg (Yield 13%), according to the sameprocedures as Preparation 53 and Example 1 except that1-acetyl-4-piperidone was used instead of cyclopentanone.

¹H-NMR (500 HMz, DMSO-d₆); δ 10.77 (brs, 1H), 7.74 (m, 2H), 7.42 (m,2H), 7.26 (m, 1H), 6.66 (d, J=1.85 Hz, 1H), 6.56 (s, 1H), 6.14 (s, 1H),5.22 (d, J=7.95, 1H), 4.28 (m, 1H), 3.82 (m, 1H), 3.62 (m, 1H), 3.13 (m,1H), 2.83 (m, 1H), 2.26 (s, 3H), 2.05 (m, 2H), 2.00 (s, 3H), 1.31 (m,2H)

Example 52 Synthesis of(5-methyl-2-phenyl-1H-indol-7-yl)-piperidin-4-yl)-amine HCl

(5-Methyl-2-phenyl-1H-indol-7-yl)-p iperidin-4-yl-amine,

The compound obtained in Preparation 19 (140 mg, 0.56 mmol) was reactedto give the title compound 50 mg (Yield 21%), according to the sameprocedures as Preparation 53 and Example 3 except that1-acetyl-4-piperidone was used instead of cyclopentanone.

Example 53 Synthesis of2-hydroxy-1-[4-(5-methyl-2-phenyl-1H-indol-7-ylamino)-piperidin-1-yl]-ethanone

2-Hydroxy-1-[4-(5-methyl-2-phenyl-1H-indol-7-ylamino)-piperidin-1-yl]-ethanone

The compound obtained in Example 52 (50 mg, 0.13 mmol) was dissolved inN,N-dimethylformamide 3 ml. Glycolic acid (15 mg, 0.20 mmol),triethylamine (0.06 ml, 0.43 mmol), EDC (38 mg, 0.20 mmol) and HOBT (27mg, 0.20 mmol) were added, and the mixture was stirred at roomtemperature for 8 hours. To the reaction mixture added 1N HCl solutionand extracted with ethylacetate. The extract was dried over anhydrousmagnesium sulfate, filtered. The filtrate was distilled under reducedpressure and purified by column chromatography to obtain the titlecompound 20 mg (Yield 43%).

¹H-NMR (500 HMz, MeOH-d₄); δ 7.72 (m, 2H), 7.38 (m, 2H), 7.23 (m, 1H),6.71 (2, 1H), 6.63 (s, 1H), 6.30 (s, 1H), 4.40 (m, 1H), 4.23 (m, 2H),3.74 (m, 2H), 3.24 (m, 1H), 3.02 (m, 1H), 2.33 (s, 3H), 2.19 (m, 2 μl),1.45 (m, 2H)

Example 54 Synthesis of(1-methanesulfonyl-piperidin-4-yl)-(5-methyl-2-phenyl-1H-indol-7-yl)-amine

(1-Methanesulfonyl-piperidin-4-yl)-(5-methyl-2-phenyl-1H-indol-7-yl)-amine

The compound obtained in Example 52 was dissolved in dichloromethane 10ml, and triethylamine (0.02 ml, 0.14 mmol), methanesulfonylchloride (10mg, 0.09 mmol) were added. The mixture was stirred at 0° C. for 1 hour.To the reaction mixture added 1N HCl solution and extracted withethylacetate. The extract was dried over anhydrous magnesium sulfate,filtered. The filtrate was distilled under reduced pressure and purifiedby column chromatography to obtain the title compound 18 mg (Yield 67%).

¹H-NMR (500 HMz, DMSO-d₆); δ 10.79 (brs, 1H), 7.74 (m, 2H), 7.42 (m,2H), 7.26 (m, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.27 (m,1H), 3.57 (m, 2H), 3.13 (m, 1H), 2.93 (m, 1H), 2.87 (s, 3H), 2.25 (s,3H), 2.14 (m, 2H), 1.46 (m, 2H)

Preparation 54: Synthesis of4-(5-methyl-2-phenyl-1H-indol-7-ylamino)-cyclohexane carboxylic acidethyl ester

The compound obtained in Preparation 19 (200 mg, 0.90 mmol) was reactedto give the title compound 170 mg (Yield 50%), according to the sameprocedures as Preparation 53 and Example 1 except that4-oxo-cyclohexanecarboxylic acid ethyl ester was used instead ofcyclopentanone.

Example 55 Synthesis of 4-(5-methyl-2-phenyl-1H-indol-7-ylamino)-cyclohexane carboxylic acid

4-(5-Methyl-2-phenyl-1H-indol-7-yla mino)-cyclohexanecarboxylic acid

The compound obtained in Preparation 54 (170 mg, 0.45 mmol) wasdissolved in the 5:1 mixture of tetrahydrofuran and methanol. 6N sodiumHydroxide 0.4 ml was added and the mixture was stirred at roomtemperature for 8 hours. At the end of reaction, the reaction mixturewas distilled under reduced pressure, diluted with 1N-hydrochloric acidsolution and extracted with ethylacetate. The extract was dried overanhydrous magnesium sulfate, filtered. The filtrate was distilled underreduced pressure and purified by column chromatography to obtain thetitle compound 120 mg (Yield 77%).

¹H-NMR (500 HMz, DMSO-d₆); δ 10.81 (brs, 1H), 7.74 (m, 2H), 7.42 (m,2H), 7.25 (m, 1H), 6.64 (d, J=2.45 Hz, 1H), 6.53 (s, 1H), 6.05 (s, 1H),5.17 (m, 1H), 3.50 (m, 2H), 2.24 (s, 3H), 1.95 (m, 1H), 1.81 (m, 2H),1.64 (m, 2H), 1.57 (m, 2H)

Example 56 Synthesis of4-(5-methyl-2-phenyl-1H-indol-7-ylamino)-cyclohexane carboxylic acid(2-morpholin-4-yl-ethyl)-amide

4-(5-Methyl-2-phenyl-1H-indol-7-yla mino)-cyclohexanecarboxylic acid(2-morpholin-4-yl-ethyl)-amide

The compound obtained in Example 55 (30 mg, 0.09 mmol) was dissolved inN, N-dimethyl formamide 5 ml. 2-Morpholine-4-yl-ethylamine (22 mg, 0.17mmol), EDC (25 mg, 0.19 mmol) and HOBT (18 mg, 0.19 mmol) were added.The mixture was stirred for 8 hours at room temperature. Saturated 1Naqueous sodium chloride solution was added, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate, filtered. The filtrate was distilled under reducedpressure and purified by column chromatography to give the titlecompound 40 mg (Yield 100%).

¹H-NMR (500 HMz, DMSO-d₆); δ 10.91 (brs, 1H), 7.75 (m, 2H), 7.65 (m,1H), 7.41 (m, 2H), 7.26 (m, 1H), 6.64 (s, 1H), 6.53 (s, 1H), 6.02 (s,1H), 5.20 (m, 1H), 3.57 (m, 2H), 3.51 (m, 5H), 3.14 (m, 2H), 2.29 (m,4H), 2.24 (s, 3H), 1.87 (m, 2H), 1.78 (m, 2H), 1.68 (m, 2H), 1.53 (m,2H)

Example 57 Synthesis ofcyclopentylmethyl-(5-methyl-2-phenyl-1H-indol-7-yl)-amine

The compound obtained from Preparation 19 (70 mg, 0.28 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 exceptthat cyclopentanecarbaldehyde was used instead of cyclopentanone to givethe title compound 36 mg (Yield 40%).

¹H-NMR (500 HMz, MeOH-d₄); δ 7.73 (m, 2H), 7.37 (m, 2H), 7.22 (m, 1H),6.68 (2, 1H), 6.62 (s, 1H), 6.18 (s, 1H), 3.14 (d, J=7.35 Hz, 2H), 2.32(s, 3H), 2.30 (m, 1H), 1.91 (m, 2H), 1.69 (m, 2H), 1.59 (m, 2H), 1.36(m, 2H)

Example 58 Synthesis of(5-methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-1-4-ylmethyl)-amine

(5-Methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl)-amine

The compound obtained from Preparation 19 (70 mg, 0.28 mmol) was reactedaccording to the same procedures as Preparation 53 and Example 1 exceptthat tetrahydro-pyran-4-carbaldehyde was used instead of cyclopentanoneto give the title compound 19 mg (Yield 21%).

¹H-NMR (500 HMz, MeOH-d₄); δ 7.73 (m, 2H), 7.38 (m, 2H), 7.23 (m, 1H),6.68 (2, 1H), 6.63 (s, 1H), 6.19 (s, 1H), 3.97 (m, 2H), 3.44 (m, 2H),3.16 (m, 2H), 2.32 (s, 3H), 1.99 (m, 1H), 1.83 (m, 2H), 1.40 (m, 2H)

Preparation 55: Synthesis of 5-Chloro-7-nitro-2-phenyl-1H-indole4-Chloro-2-nitroaniline (1.0 g, 3.67 mmol) was reacted instead of4-methyl-2-nitroaniline in Preparation 19 to give the title compound 750mg (Yield 75%) Example 59 Synthesis of(5-chloro-2-phenyl-1H-indol-7-yl)-cyclopentyl-amine

(5-Chloro-2-phenyl-1H-indol-7-yl)-c yclopentyl-amine

5-Chloro-7-nitro-2-phenyl-1H-indole (225 mg, 0.83 mmol) was reactedinstead of 5-methyl-7-nitro-2-phenyl-1H-indole in Preparation 46 to givethe title compound 230 mg (Yield 89%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.04 (brs, 1H), 7.75 (m, 2H), 7.45 (m,2H), 7.30 (m, 1H), 6.76 (d, J=1.8 Hz, 1H), 6.72 (d, J=2.45 Hz, 1H), 6.14(d, J=1.8 Hz, 1H), 3.84 (m, 1H), 2.00 (m, 2H), 1.71 (m, 2H), 1.60 (m,2H), 1.52 (m, 2H)

Example 60 Synthesis of(5-chloro-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

(5-Chloro-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

5-Chloro-7-nitro-2-phenyl-1H-indole (337 mg, 1.23 mmol) was reactedinstead of 5-methyl-7-nitro-2-phenyl-1H-indole in Preparation 49 to givethe title compound 200 mg (Yield 50%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.09 (brs, 1H), 7.74 (m, 2H), 7.43 (m,2H), 7.29 (m, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 6.24 (s, 1H), 5.60 (m,1H), 4.28 (m, 1H), 3.86 (m, 2H), 3.43 (m, 2H), 1.96 (m, 2H), 1.41 (m,2H)

Example 61 Synthesis of(5-chloro-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl)-amine

(5-Chloro-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl)-amine

5-Chloro-7-nitro-2-phenyl-1H-indole (337 mg, 1.23 mmol) was reactedinstead of 5-methyl-7-nitro-2-phenyl-1H-indole in Preparation 50 to givethe title compound 288 mg (Yield 69%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.06 (brs, 1H), 9.57 (brs, 1H), 7.75 (m,2H), 7.45 (m, 2H), 7.31 (m, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 6.29 (s,1H), 3.66 (m, 1H), 3.49 (m, 2H), 3.11 (m, 2H), 2.78 (s, 3H), 2.23 (m,2H), 1.61 (m, 2H)

Example 62 Synthesis of(5-chloro-2-phenyl-1H-indol-7-yl)-cyclohexyl-amine

(5-Chloro-2-phenyl-1H-indol-7-yl)-c yclohexyl-amine

The compound obtained from Preparation 55 (170 mg, 0.62 mmol) wasreacted to give the title compound 98 mg (Yield 49%), according to thesame procedures as Preparation 53 and Example 1 except thatcyclohexanone was used instead of cyclopentanone.

¹H-NMR (500 HMz, CDCl₃); δ 8.18 (brs, 1H), 7.65 (m, 2H), 7.44 (m, 5H),7.31 (m, 2H), 7.03 (s, 1H), 6.70 (s, 1H), 6.47 (d, 1H), 3.38 (m, 1H),2.16 (m, 2H), 1.81 (m, 2H), L 71 (m, 1H), 1.42 (m, 2H), 1.24 (m, 4H)

Example 63 Synthesis of(1-benzyl-pyrrolidin-3-yl)-(5-chloro-2-phenyl-1H-indol-7-yl)-amine

(1-Benzyl-pyrrolidin-3-yl)-(5-chlor o-2-phenyl-1H-indol-7-yl)-amine

The compound obtained from Preparation 55 (225 mg, 0.83 mmol) wasreacted to give the title compound 50 mg (Yield 15%), according to thesame procedures as Preparation 53 and Example 1 except that1-benzyl-pyrrolidine-3-one was used instead of cyclopentanone.

¹H-NMR (500 HMz, CDCl₃); δ 10.33 (brs, 1H), 7.83 (m, 2H), 7.47 (m, 5H),7.41 (m, 2H), 7.28 (m, 1H), 7.00 (d, J=1.85 Hz, 1H), 6.69 (d, J=1.85 Hz,1H), 6.19 (d, J=1.8, 1H), 4.49 (m, 1H), 4.36 (d, J=12.8 Hz, 2H), 4.09(d, J=12.8 Hz, 2H), 3.82 (m, 1H), 3.59 (m, 1H), 3.18 (m, 1H), 3.11 (m,1H), 2.41 (m, 2H)

Preparation 56: Synthesis of 4-ethynyl-benzoic acid methyl ester

(Step 1)

20.60 g (78.61 mmol) of 4-Iodobenzoic acid methyl ester and 9.26 g(94.33 mmol) of ethynyl trimethylsilane were dissolved in 200 ml oftetrahydrofuran, and thereto 23.86 g (235.83 mmol) of triethylamine,1.65 g (2.36 mmol) of dichloro(bistriphenylphosphine)palladium(II) and0.45 g (2.36 mmol) of cupper(I) iodide were added. The mixture wasstirred at room temperature for 8 hours. At the end of reaction, addedwater and extracted with ethylacetate. The extract was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and separated by column chromatography to obtaintrimethylsilylethynylbenzoic acid methyl ester 18.30 g (Yield 100%).

(Step 2)

The compound obtained in Step 1 (18.30 g, 78.61 mmol) was dissolved in300 ml of the 2:1 mixture of methanol and dichloromethane, and 5.44 g(39.3 mmol) of potassium carbonate was added. The mixture was stirred atroom temperature for 1 hour. At the end of reaction, the reactionmixture was diluted with water and extracted with ethylacetate. Theextract was washed with saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and separated by column chromatography toobtain the title compound 11.90 g (Yield 95%).

Preparation 57: Synthesis of 4-(5-Chloro-2-nitro-1H-indol-2-yl)-benzoicacid methyl ester

(Step 1)

2-Iodo-4-chloro-6-nitro-phenylamine (10.0 g, 33.50 mmol) of wasdissolved in 200 ml of tetrahydrofuran, and 3.97 g (50.25 mmol) ofpyridine and 7.74 g (36.85 mmol) of trifluoroacetic anhydride wereadded. The mixture was stirred for 9 hours at 0° C.˜room temperature. Atthe end of reaction, the reaction mixture was diluted with water andextracted with ethylacetate. The extract was washed with saturatedsodium chloride solution, dried over anhydrous magnesium sulfate, andseparated by column chromatography to obtain trifluoroacetamide 12.3 g(Yield 85%).

(Step 2)

The compound obtained in Step 1 (12.3 g, 31.18 mmol) and 6.0 g (37.42mmol) of 4-ethynylbenzoic acid methyl ester were dissolved in 200 ml ofN,N-dimethylformamide 9.47 g (93.54 mmol) of Triethylamine and 11.51 g(31.18 mmol) of tetrabutylammoniumiodide, 1.09 g (1.56 mmol) ofdichloro(bistriphenylphosphine)palladium(II) and 0.30 g (1.56 mmol) ofcupper(I) iodide were added. The mixture was stirred at 80° C. for 8hours. At the end of reaction, the reaction mixture was diluted withwater and extracted with ethylacetate. The extract was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and separated by column chromatography to obtain the titlecompound 7.6 g (Yield 81%).

Example 64 Synthesis of4-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-benzoic acid methyl ester

4-(5-Chloro-7-cyclopentylamino-1H-i ndol-2-yl)-benzoic acid methyl ester

The compound obtained in Preparation 57 (7.60 g, 22.98 mmol) was reactedinstead of 5-methyl-7-nitro-2-phenyl-1H-indole in Preparation 46 to givethe title compound 1.25 g (Yield 15%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.25 (brs, 1H), 8.07 (d, J=8 Hz, 2H), 7.94(d, J=8 Hz, 2H), 6.95 (s, 1H), 6.84 (s, 1H), 6.22 (s, 1H), 5.77 (d, J=8Hz, 1H), 3.89 (s, 3H), 3.88 (m, 1H), 2.05 (m, 2H), 1.75 (m, 2H), 1.65(m, 2H), 1.63 (m, 2H)

Example 65 Synthesis of4-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-benzoic acid

4-(5-Chloro-7-cyclopentylamino-1H-i ndol-2-yl)-benzoic acid

The compound obtained in Example 64 (300 mg, 0.81 mmol) was dissolved in15 ml of tetrahydrofuran, 5 ml of water and 5 ml of methanol. 100 mg(2.44 mmol) of Lithium hydroxide monohydrate was added. The mixture wasstirred at room temperature for 21 hours. At the end of reaction,tetrahydrofurane and methanol were removed by distillation under reducedpressure. To the distillate 1N HCl solution was added the mixture wasextracted with ethylacetate. The extract was washed with saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,filtered. The filtrate was distilled under reduced pressure, andseparated by column chromatography to obtain the title compound 20 mg(Yield 7%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.59 (brs, 1H), 8.01 (m, 4H), 6.94 (d,J=12 Hz, 2H), 6.31 (s, 1H), 3.91 (m, 1H), 2.01 (m, 2H), 1.77 (m, 2H),1.62 (m, 4H)

Example 66 Synthesis of[4-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-phenyl]-methanol

[4-(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-phenyl]-methanol

The compound obtained in Example 64 (760 mg, 2.06 mmol) was dissolved in30 ml of tetrahydrofuran and 2M-lithiumborohydride solution intetrahydrofuran (2.06 ml, 4.12 mmol) was added. The mixture was at 80°C. for 3 hours. Saturated ammoniumchloride solution was added and themixture was extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate, filtered. The filtrate was distilled underreduced pressure, and purified by column chromatography to obtain thetitle compound 60 mg (Yield 9%).

¹H-NMR (400 HMz. DMSO-d₆); δ 11.04 (brs, 1H), 7.75 (d, J=8 Hz, 2H), 7.42(d, J=8 Hz, 2H), 6.78 (s, 1H), 6.73 (s, 1H), 6.17 (s, 1H), 5.71 (d, J=3Hz, 1H), 5.23 (t, 1H), 4.54 (d, J=4 Hz, 1H), 4.02 (m, 1H), 2.02 (m, 2H),1.75 (m, 2H), 1.63 (m, 2H), 1.55 (m, 2H)

Example 67 Synthesis of4-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-benzoic acid methyl ester

4-(7-Cyclopentylamino-5-methyl-1H-i ndol-2-yl)-benzoic acid methyl ester

2-Iodo-4-methyl-6-nitro-phenylamine (500 mg, 1.80 mmol) was reactedinstead of 2-iodo-4-chloro-6-nitro-phenylamine according to the sameprocedures as Preparation 57 and Example 64 to give the title compound30 mg (Yield 3%).

Preparation 58: Synthesis of 2-(5-chloro-7-nitro-1H-indol-2-yl)-benzoicacid methyl ester

2-Ethynyl-benzoic acid methyl ester (6.0 g 37.42 mmol) was reactedinstead of 4-Ethynyl-benzoic acid methyl ester in Preparation 57 to givethe title compound 1.8 g (Yield 15%).

¹H-NMR (400 HMz, CDCl₃); δ 10.88 (brs, 1H), 8.15 (s, 1H), 7.94 (d, 2H),7.70 (s, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 6.76 (s, 1H), 3.88 (s, 3H)

Example 68 Synthesis of2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-benzoic acid methyl ester

2-(5-Chloro-7-cyclopentylamino-1H-i ndol-2-yl)-benzoic acid methyl ester

The compounds obtained in Preparation 58 (1.80 g, 5.44 mmol) was reactedinstead of 5-methyl-7-nitro-2-phenyl-1H-indole in Example 46 to give thetitle compound 800 mg (Yield 40%).

¹H-NMR (400 HMz, CDCl₃); δ 9.81 (brs, 1H), 7.71 (d, J=4 Hz, 1H), 7.59(d, J=4 Hz, 1H), 7.43 (t, 1H), 7.30 (t, 1H), 6.97 (s, 1H), 6.50 (d, J=2Hz, 1H), 6.36 (d, J=2 Hz, 1H), 3.89 (s, 3H), 3.86 (m, 1H), 2.12 (m, 2H),1.77 (m, 2H), 1.67 (m, 2H), 1.60 (m, 2H)

Example 69 Synthesis of2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-benzoic acid

2-(5-Chloro-7-cyclopentylamino-1H-i ndol-2-yl)-benzoic acid

The compound obtained in Example 68 (300 mg, 0.81 mmol) was reactedaccording to the same procedures as Example 65 to give the titlecompound 120 mg (Yield 42%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.57 (brs, 1H), 7.71 (m, 2H), 7.61 (m,2H), 7.50 (m, 1H), 7.07 (s, 1H), 6.53 (s, 1H), 6.48 (s, 1H), 3.97 (m,1H), 2.00 (m, 2H), 1.76 (m, 2H), 1.67 (m, 4H)

Example 70 Synthesis of[2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-phenyl]-methanol

[2-(5-Chloro-7-cyclopentylamino-1H-indol-2-yl)-phenyl]-methanol

The compound obtained in Example 68 (300 mg, 0.81 mmol) was reactedaccording to the same procedures as Example 66 to give the titlecompound 150 mg (Yield 54%).

¹H-NMR (400 HMz, CDCl₃); δ 11.37 (brs, 1H), 7.69 (d, J=8 Hz, 1H), 7.47(m, 2H), 7.42 (m, 2H), 7.21 (s, 1H), 6.69 (s, 1H), 4.78 (s, 2H), 3.97(m, 1H), 1.96 (m, 4H), 1.86 (m, 2H), 1.56 (m, 2H)

Preparation 59: Synthesis of 7-nitro-2-phenyl-1H-indol-5-carboxylic acidethyl ester

4-Amino-3-nitro-benzoic acid ester (3.0 g, 8.9 mmol) was reacted insteadof 4-methyl-2-nitroaniline in Preparation 19 to give the title compound1.6 g (Yield 58%).

¹H-NMR (500 HMz, CDCl₃); δ 10.23 (brs, 1H), 8.82 (s, 1H), 8.65 (s, 1H),7.74 (m, 2H), 7.52 (m, 2H), 7.44 (m, 1H), 7.02 (s, 1H), 4.45 (q, 2H),1.45 (t, 3H)

Example 71 Synthesis of7-cyclopenthylamino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester

7-Cyclopentylamino-2-phenyl-1H-indo le-5-carboxylic acid ethyl ester

The compound obtained in Preparation 59 (600 mg, 1.9 mmol) was reactedinstead of 5-methyl-7-nitro-2-phenyl-1H-indole in Example 46 to give thetitle compound 100 mg (Yield 15%).

¹H-NMR (400 HMz, CDCl₃); δ 9.47 (brs. 1H), 7.90 (s, 1H), 7.67 (m, 2H),7.34 (m, 2H), 7.24 (m, 1H), 7.18 (s, 1H), 6.83 (s, 1H), 4.41 (q, 2H),3.87 (m, 1H), 1.95 (m, 2H), 1.62 (m, 2H), 1.49 (m, 4H), 1.39 (t, 3H)

Example 72 Synthesis of7-cyclopenthylamino-2-phenyl-1H-indole-5-carboxylic acid

7-Cyclopentylamino-2-phenyl-1H-indo le-5-carboxylic acid

The compound obtained in Example 71 (350 mg, 1.0 mmol) was reactedaccording to the same procedures as Example 65 to give the titlecompound 300 mg (Yield 94%).

¹H-NMR (400 HMz, MeOH-d₄); δ 7.88 (s, 1H), 7.75 (m, 2H), 7.42 (m, 2H),7.30 (m, 1H), 7.16 (s, 1H), 6.85 (s, 1H), 4.03 (m, 1H), 2.13 (m, 2H),1.77 (m, 2H), 1.66 (m, 4H)

Example 73 Synthesis of(7-cyclopenthylamino-2-phenyl-1H-indol-5-yl)-methanol

(7-Cyclopentylamino-2-phenyl-1H-ind ol-5-yl)-methanol

The compound obtained in Example 71 (60 mg, 0.17 mmol) was reactedaccording to the same procedures as Example 66 to give the titlecompound 21 mg (Yield 40%).

¹H-NMR (400 HMz, MeOH-d₄); δ 7.88 (s, 1H), 7.75 (m, 2H), 7.42 (m, 2H),7.30 (m, 1H), 7.16 (s, 1H), 6.85 (s, 1H), 4.03 (m, 1H), 2.13 (m, 2H),1.77 (m, 2H), 1.66 (m, 4H)

Preparation 60: Synthesis of (7-nitro-2-phenyl-1H-indol-5-yl)-aceticacid ethyl ester

(4-Amino-3-nitro-phenyl)acetic acid ethyl ester (4.8 g, 13.7 mmol) wasreacted instead of 4-methyl-2-nitroaniline in Preparation 19 to give thetitle compound 3.0 g (Yield 68%).

¹H-NMR (500 HMz, CDCl₃); δ 10.03 (brs, 1H), 8.05 (s, 1H), 8.00 (s, 1H),7.72 (m, 2H), 7.49 (m, 2H), 7.49 (m, 1H), 7.39 (m, 1H), 6.87 (s, 1H),4.19 (q, 2H), 2.04 (s, 2H), 1.26 (t, 3H)

Example 74 Synthesis of(7-cyclopenthylamino-2-phenyl-1H-indol-5-yl)-acetic acid ethyl ester

(7-Cyclopentylamino-2-phenyl-1H-ind ol-5-yl)-acetic acid ethyl ester

The compound obtained in Preparation 60 (3.0 g, 9.2 mmol) was reactedinstead of 5-methyl-7-nitro-2-phenyl-1H-indole in Example 46 to give thetitle compound 2.0 g (Yield 60%).

¹H-NMR (400 HMz, CDCl₃); δ 8.12 (brs, 1H), 7.67 (m, 2H), 7.42 (m, 2H),7.30 (m, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 6.46 (s, 1H), 4.16 (q, 2H),3.93 (m, 1H), 3.66 (s, 2H), 2.10 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H),1.59 (t, 3H), 1.26 (t, 3H)

Example 75 Synthesis of(7-cyclopenthylamino-2-phenyl-1H-indol-5-yl)-acetic acid

(7-Cyclopentylamino-2-phenyl-1H-ind ol-5-yl)-acetic acid

The compound obtained in Preparation 74 (90 mg, 0.25 mmol) was reactedaccording to the same procedures as Example 65 to give the titlecompound 65 mg (Yield 78%).

¹H-NMR (400 HMz, CDCl₃+MeOH-d₄); δ 11.31 (s, 1H), 7.81 (m, 2H), 7.37 (m,2H), 7.25 (m, 1H), 7.05 (s, 1H), 6.65 (s, 1H), 3.89 (m, 1H), 1.88 (m,7H), 1.41 (m, 3H)

Example 76 Synthesis of2-(7-cyclopenthylamino-2-phenyl-1H-indol-5-yl)-ethanol

2-(7-Cyclopentylamino-2-phenyl-1H-i ndol-5-yl)-ethanol

The compound obtained in Preparation 74 (50 mg, 0.14 mmol) was reactedaccording to the same procedures as Example 66 to give the titlecompound 40 mg (Yield 89%).

¹H-NMR (400 HMz, CDCl₃+MeOH-d₄); δ 7.71 (m, 2H), 7.40 (m, 2H), 7.28 (m,1H), 6.89 (s, 1H), 6.72 (s, 1H), 6.32 (s, 1H), 3.97 (m, 1H), 3.87 (m,2H), 3.43 (m, 1H), 2.91 (m, 2H), 2.09 (m, 2H), 1.77 (m, 2H), 1.62 (m,4H)

Example 77˜90

The nitro indole compounds produced in Preparations 5, 7 and 10, thecompounds produced in Preparations 23 and 25, and the commerciallyavailable ketone compounds were reacted according to the procedures asPreparation 34, 35, 36 and Example 11 in the order to give the followingexemplary compounds.

Example * R1 R4 ¹H NMR data 77 S (tetrahydropyran- methyl (400 MHz ,CDCl₃); δ 11.92 ( br s, 1H), 6.98 (s, 4-yl)methyl 1H), 6.77 (s, 1H),6.22 (s, 1H), 6.29 (br s, 1H), 3.96 (m, 2H), 3.70 (m, 1H), 3.37 (m, 2H),3.18 (m, 1H), 3.08 (m, 2H), 2.729m, 1H), 2.56 (m, 1H), 2.37 (s, 3H),1.91 (m, 1H), 1.75 (m, 2H), 1.41 (m, 2H) 78 S (tetrahydropyran- chloro(500 MHz, DMSO-d₆); δ 11.52 (br s, 1H), 6.80 (s, 4-yl)methyl 1H), 6.69(s, 1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.94 (m, 1H), 3.81 (m, 1H), 3.63(m, 1H), 3.45 (m, 1H), 3.38 (m, 3H), 3.14 (m, 1H), 2.85 (m, 1H), 1.93(m, 2H), 1.68 (m, 2H), 1.48 (m, 10H) 79 S 4,4-difluorocyclo methyl (400MHz, CDCl₃); δ 11.94 (brs, 1H), 7.00 (s, hexyl 1H), 6.78 (s, 1H), 6.26(s, 1H), 5.35 (m, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 3.22 (m, 1H), 2.75(m, 1H), 2.62 (m, 1H), 2.37 (s, 3H), 2.25 (m, 1H), 2.09-1.73 (m, 7H) 80S tetrahydropyran- OPh (400 MHz, CDCl₃); δ 11.95 (brs, 1H), 7.28 (m,4-yl 2H), 7.06-6.96 (m, 4H), 6.58 (s, 1H), 6.24 (s, 1H), 5.33 (m, 1H),3.98 (m, 2H), 3.75 (m, 1H), 3.58-3.47 (m, 3H), 3.23 (d, 1H), 2.78-2.62(m, 2H), 2.04 (m, 2H), 1.58 (m, 2H) 81 R tetrahydropyran- OPh (400 MHz,CDCl₃); δ 11.98 (br s, 1H), 7.28 (m, 4-yl 2H), 7.00 (m, 4H), 6.58 (s,1H), 6.22 (s, 1H), 5.34 (m, 1H), 3.98 (m, 2H), 3.70 (m, 1H), 3.50 (m,3H), 3.21 (m, 2H), 2.74 (m, 1H), 2.66 (m, 1H), 2.05 (m, 2H), 1.58 (m,2H) 82 R (tetrahydropyran- H (400 MHz, CDCl₃); δ 11.96 (br s, 1H), 7.30(m, 4-yl)methyl 2H), 7.03 (m, 4H), 6.60 (s, 1H), 6.20 (s, 1H), 5.36 (m,1H), 3.93 (m, 1H), 3.73 (m, 1H), 3.35 (m, 2H), 3.23 (m, 1H), 3.06 (m,2H), 2.72 (m, 1H), 2.52 (m, 1H), 1.92 (m, 1H), 1.73 (m, 2H), 1.40 (m,2H) 83 S Cyclopentyl H (400 MHz, CDCl₃); δ 11.74 (brs, 1H), 7.06 (s,1H), 6.99 (m, 2H), 6.45 (s, 1H), 5.48 (m, 1H), 3.90 (m, 1H), 3.71 (m,1H), 3.23 (m, 1H), 2.75 (m, 1H), 2.67 (m, 1H), 2.04 (m, 2H), 1.75 (m,2H) 1.61-1.48 (m, 4H) 84 S 1-acetyl-pyrrolidin- H (400 MHz, CDCl₂); δ10.13 (brs, 1H), 6.93 (s, 3-yl 1H), 6.82 (s, 1H), 6.38 (s, 1H), 5.09 (m,1H), 4.16 (m, 1H), 3.67 (m, 2H), 3.52 (m, 2H), 3.38 (m, 1H), 3.25 (m,1H), 2.91 (m, 1H), 2.66 (m, 1H), 2.48 (s, 3H), 2.23 (m, 1H), 2.00 (m,1H), 85 S (tetrahydropyran- H (400 MHz, CDCl₃); δ 11.89 (brs, 1H), 7.13(s, 4-yl)methyl 1H), 7.04 (m, 2H), 6.44 (m, 1H), 5.39 (m, 1H), 3.98 (m,2H), 3.77 (m, 1H), 3.41 (m, 2H), 3.25 (m, 1H), 3.13 (m, 2H), 2.78 (m,1H), 2.64 (m, 1H), 2.00 (m, 1H), 1.79 (m, 2H), 1.44 (m, 2H), 86 Stetrahydrofuran- H (400 MHz, CDCl₃); δ 11.87 (brs, 1H), 7.15 (s, 3-yl1H), 7.03 (m, 2H), 6.50 (m, 1H), 5.39 (m, 1H), 4.06 (m, 2H), 3.80-3.62(m, 2H), 3.57 (m, 2H), 3.29 (m, 1H), 2.83 (m, 1H), 2.69 (m, 1H), 2.11(m, 2H), 1.64 (m, 2H) 87 S (tetrahydropyran- H (400 MHz, CDCl₃); δ 11.68(brs, 1H), 7.06-6.98 2-yl)methyl (m, 3H), 6.45 (s, 1H), 5.32 (m, 1H),3.96 (m, 1H), 3.77-3.61 (m, 2H), 3.43 (m, 1H), 3.28-3.21 (m, 3H), 2.80(m, 1H), 2.65 (m, 1H), 1.83 (m, 1H), 1.71 (m, 1H), 1.62-1.42 (m, 4H) 88S 1-trifluroromethyl methyl (400 MHz, CDCl₃); δ 11.94 (brs, 1H), 6.98(s, carbony-piperidin- 1H), 6.78 (s, 1H), 6.25 (s, 1H), 5.33 (m, 1H),4-yl 4.13 (m, 1H), 3.76-3.68 (m, 5H), 3.47-3.41 (m, 3H), 2.74-2.63 (m,2H), 2.36 (s, 3H), 2.04 (m, 2H), 1.56 (m, 2H) 89 R Cyclopentyl (400 MHz,CDCl₃); δ 10.62 (br s, 1H), 7.04 (d, 1H), 6.97 (t, 1H), 6.92 (d, 1H)6.49 (d, 1H), 5.20 (m, 1H), 3.83 (m, 2H), 3.64 (m, 1H), 3.39 (m, 1H),3.31 (m, 1H), 3.17 (m, 1H), 3.01 (m, 1H), 1.97 (m, 4H), 1.73 (m, 4H),1.60 (m, 6H), 1.46 (m, 2H), 1.34 (m, 2H) 90 R (tetrahydropyran- methyl(400 MHz, CDCl₃); δ 11.54 (brs, 1H), 7.11 (s, 4-yl)methyl 1H), 6.80 (s,1H), 6.22 (s, 1H), 5.29 (m, 1H), 3.92 (m, 2H), 3.68 (m, 1H), 3.35 (m,2H), 3.21- 3.04 (m, 3H), 2.84-2.52 (m, 2H), 2.32 (s, 3H), 1.90 (m, 1H),1.74 (m, 2H), 1.35 (m, 2H)

Example 91˜101

The esters obtained during the process of Example 21, 77, 79, 89 and 78were reduced according to the procedures as Example 4 and then reactedaccording to the procedures as Preparation 37 and Example 15 to give thefollowing exemplary compounds.

Example R2′ * R1 R4 NMR 91 2-oxopipe- S (tetrahydro methyl (500 MHz,CDCl₃); δ 11.03 (s, 1H), 8.20 (br razin-4-yl pyran-4-yl) s, 1H), 6.82(s, 1H), 6.79 (s, 1H), 6.31 methyl (s, 1H), 4.71 (br s, 2H), 4.24 (m,1H), 3.91 (m, 2H), 3.80-3.51 (m, 4H), 3.31 (m, 2H), 3.20 (m, 1H), 3.14(d, 2H), 2.95 (m, 2H), 2.70 (m, 1H), 2.41 (m, 1H), 2.40 (s, 3H), 2.20(m, 1H), 2.00 (m, 1H), 1.81 (d, 2H), 1.40 (m, 2H) 92 1,1-dioxo S(tetrahydro methyl (500 MHz, CDCl₃); δ 9.47 (br s, 1H), 6.88 thiomorpyran-4-yl) (s, 1H), 6.47 (s, 1H), 6.39 (s, 1H), 5.87 pholin-4- methyl(br s, 1H), 4.12-4.00 (m, 2H), 3.85 (br s, yl 4H), 3.66 (m, 1H), 3.58(t, 2H), 3.08 (br s, 4H), 2.95 (m, 1H), 2.85-2.70 (m, 3H), 2.41 (s, 3H),2.10 (m, 2H), 1.96 (m, 2H), 1.60 (m, 2H) 93 morpholin- S 4,4-difluoromethyl (400 MHz, CDCl₃); δ 9.67 (brs, 1H), 6.87 4-yl cyclohexyl (s, 1H),6.82 (s, 1H), 6.34 (s, 1H), 4.71 (m, 1H), 3.65 (m, 6H), 3.55 (dd, J = 8Hz, 1H), 3.51 (m, 1H), 3.15 (dd, J = 8 Hz, 1H), 2.52-2.29 (m, 9H),2.15-2.04 (m, 4H), 1.96-1.90 (m, 2H), 1.58-1.51 (m, 2H) 94 2-oxopipe- S4,4-difluoro methyl (400 MHz, CDCl₃); δ 10.14 (brs, 1H), 6.82 razin-4-ylcyclohexyl (s, 1H), 6.80 (s, 1H), 6.31 (s, 1H), 4.65 (m, 1H), 3.54 (m,1H), 3.53 (dd, J = 8 Hz, 1H), 3.39 (m, 2H), 3.30 (m, 1H), 3.22-3.08 (m,4H), 2.78-2.65 (m, 4H), 2.38 (s, 3H), 2.28-2.04 (m, 4H), 1.96-1.86 (m,2H), 1.73 (m, 2H) 95 2-oxopipe- S (tetrahydro OPh (400 MHz, CDCl₃); δ10.70 (brs, 1H), 7.20 razin-4-yl pyran-4-yl) (m, 2H), 7.01 (m, 3H), 6.85(m, 1H), 6.80 methyl (d, 1H), 6.60 (m, 1H), 6.20 (m, 1H), 5.03 (m, 1H),4.70 (m, 1H), 3.78 (m, 2H), 3.55 (m, 1H), 3.48-3.30 (m, 6H), 3.15-3.10(m, 4H), 2.81 (m, 1H), 2.71 (m, 3H), 1.94 (m, 3H), 1.72 (m, 2H), 1.42(m, 2H). 96 morpholin- S (tetrahydro OPh (400 MHz, CDCl₃); δ 10.19 (brs,1H), 7.29 4-yl pyran-4-yl) (m, 2H), 7.02 (m, 3H), 6.84 (s, 1H), 6.65methyl (s, 1H), 6.26 (s, 1H), 4.77 (m, 1H), 3.94 (m, 2H), 3.83 (m, 1H),3.63-3.55 (m, 6H), 3.36 (m, 2H), 3.19 (m, 1H), 3.04 (m, 2H), 2.46 (m,2H), 2.34 (m, 4H), 2.01 (m, 1H), 1.84 (m, 2H), 1.59 (m, 2H), 1.28 (m,2H) 97 morpholin- S (tetrahydro methyl (500 MHz, CDCl₃); δ 11.13 (s, 1H)6.82 (d, 4-yl pyran-4-yl) 2H), 6.24 (s, 1H), 4.81-4.78 (m, 1H), 3.88-methyl 3.81 (m, 2H), 3.60-3.46 (m, 5H), 3.35- 3.30 (m, 2H), 3.19-3.17(m, 1H), 3.01 (br, 2H), 2.38-2.26 (m, 7H), 2.14 (s, 2H), 1.91-1.88 (m,1H), 1.75-1.71 (m, 2H), 1.53-1.47 (m, 2H), 1.28-1.16 (m, 2H) 981-carbamoyl- S (tetrahydro methyl (400 MHz, CDCl₃); δ 11.22 (s, 1H),7.16 piperazin- pyran-4-yl) (s, 1H), 6.60 (d, 2H), 6.07 (s, 1H), 5.724-yl methyl (s, 2H), 4.58 (m, 1H), 3.87-3.85 (m, 2H), 3.57-3.50 (m, 2H),3.28 (m, 2H), 3.16-3.11 (m, 2H), 3.01-3.00 (m, 2H), 2.87 (m, 2H),2.40-2.35 (m, 1H), 2.24 (s, 3H), 2.02-1.94 (m, 2H), 1.88-1.81 (m, 2H),1.75-1.72 (m, 2H), 1.65-1.63 (m, 2H), 1.56-1.50 (m, 2H), 1.28-1.21 (m,2H) 99 2-hydroxy- S (tetrahydro methyl (400 MHz, CDCl₃); δ 10.25 (s,1H), 6.76 mehtyl- pyran-4-yl) (s, 1H), 6.74 (s, 1H), 6.23 (s, 1H), 4.67-pyrrolidin- methyl 4.58 (m, 2H), 4.16-4.09 (m, 1H), 4.00-3.94 1-yl (m,2H), 3.73-3.68 (m, 1H), 3.50-3.36 (m, 2H), 3.11 (d, 2H), 2.99-2.94 (m,2H), 2.32 (s, 3H), 2.15-2.07 (m, 2H), 2.02-1.92 (m, 3H), 1.76-1.73 (m,2H), 1.42-1.36 (m, 2H), 1.14-1.08 (m, 2H), 0.86-0.81 (m, 2H), 0.73-0.68(m, 2H) 100 2-carbamoyl- S (tetrahydro methyl (400 MHz, CDCl₃); δ 11.31(s, 1H), 8.18 pyrrolidin- pyran-4-yl) (br, 1H), 7.24 (d, 1H), 6.83 (s,1H), 6.75 l-yl methyl (s, 1H), 6.22 (s, 1H), 5.50 (br, 1H), 4.71-4.64(m, 1H), 4.07-3.99 (m, 2H), 3.57-3.38 (m, 3H), 3.28-3.25 (m, 1H),3.19-3.06 (m, 4H), 2.88-2.81 (m, 1H), 2.75-2.70 (m, 1H), 2.49-2.41 (m,1H), 2.39 (s, 3H) 2.25-2.12 (m, 1H), 2.08-2.04 (m, 1H), 1.99-1.95 (m,2H), 1.83-1.80 (m, 4H), 1.53-1.40 (m, 2H) 101 2-oxopipe- R Cyclopentylmethy (400 MHz, CDCl₃); δ 10.28 (brs, 1H), 6.83 razin-4-yl (s, 1H), 6.58(s, 1H), 6.33 (s, 1H), 4.73 (m, 1H), 3.91 (m, 1H), 3.55 (m, 1H), 3.48-3.10 (m, 3H), 2.68-2.58 (m, 4H), 2.40 (s, 3H), 2.19-1.98 (m, 3H), 1.93(m, 1H), 1.78-1.58 (m, 8H)

Preparation 61: Synthesis of[(S)-2-(5-methyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-oxazol-4-yl]-aceticacid isopropyl ester

(Step 1)

5-Methyl-7-nitro-1H-indole-2-carboxylic acid methyl ester obtained inPreparation 7 was hydrolyzed using LiOH according to the same proceduresas Step 1 of Preparation 28 to give5-methyl-7-nitro-1H-indole-2-carboxylic acid.

(Step 2)

(S)-3-t-Butoxycarbonylamino-4-hydroxybutyric acid-isopropyl ester usedin Preparation 25 was deprotected according to the same procedures asStep 3 of Preparation 24 to give (S)-3-amino-4-hydroxy-butyric acidisopropyl ester.

(Step 3)

The compounds obtained in Step 1 and 2 were reacted according to thesame procedures as Step 2 of Preparation 28 to give(S)-4-hydroxy-3-[(5-methyl-7-nitro-1H-indole-2-carbonyl)-amino]-butyricacid isopropyl ester.

(Step 4)

The compound obtained in Step 3 and methanesulfonyl chloride werereacted according to the same procedures as Preparation 33 to give(S)-4-methansulfonyloxy-3-[(5-methyl-7-nitro-1H-indole-2-carbonyl)-amino]-butyricacid isopropyl ester.

(Step 5)

The compound obtained in Step 4 (890 mg, 2 mmol) was added to THF (10mL), K₂CO₃ (330 mg, 10 mmol) was added. The mixture was stirred at 80°C. for 2 hours. Water was added to quench the reaction. The mixture wasextracted with EtOAc, dried over MgSO₄, and solvent was removed underreduced pressure. The residue was purified by column chromatography(eluent: EtOAc/n-Hex/DMC=1/4/1) to give the title compound (445 mg,Yield 61%).

Example 102 Synthesis of[(S)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-oxazol-4-yl]-aceticacid

[(S)-2-(7-Cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-oxazol-4-yl]-aceticacid

The procedures of Step 3 of Preparation 31, Preparation 36 and Step 1 ofPreparation 28 were conducted in the order using the compound obtainedin Preparation 61 and cyclopentanone to give the title compound.

¹H-NMR (400 MHz, CDCl₃/MeOH-d₄); δ, 6.97 (s, 1H), 6.79 (s, 1H), 6.33 (s,1H), 4.86 (m, 1H), 4.62 (dd, 1H), 4.35 (dd, 1H), 3.95 (m, 1H), 2.94 (dd,1H), 2.67 (dd, 1H), 2.39 (s, 3H), 2.07 (m, 2H), 1.78 (m, 2H), 1.65 (m,4H)

Example 103 Synthesis of[(S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-oxazol-4-yl}-aceticacid

{(S)-2-[5-Methyl-7-(tetrahydro-pyra n-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-oxazol-4-yl}acetic acid

Tetrahydropyran-4-one was used instead of cyclopentanone in Example 102to give the title compound.

¹H-NMR (400 MHz, CDCl₃/MeOH-d₄); δ 6.94 (s, 1H), 6.81 (s, 1H), 6.32 (s,1H), 4.87 (m, 1H), 4.59 (dd, 1H), 4.34 (dd, 1H), 4.02 (d, 1H), 3.68˜3.58(m, 3H), 2.92 (dd, 1H), 2.68 (dd, 1H), 2.38 (s, 3H), 2.13 (d, 2H), 1.57(m, 2H)

Example 104 Synthesis of{(S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-oxazol-4-yl}-ethanol

2-{(S)-2-[5-Methyl-7-(tetrahydro-py ran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-oxazol-4-yl}-ethanol

The compound obtained in Example 103 was reduced to give the titlecompound according to the same method as Example 66.

¹H-NMR (400 MHz, CDCl₃); δ 10.11 (br s, 1H), 6.91 (s, 1H), 6.86 (s, 1H),6.34 (s, 1H), 4.60 (t, 1H), 4.48 (m, 1H), 4.10˜3.93 (m, 5H), 3.63˜3.52(m, 3H), 2.39 (, 3H), 2.07 (d, 2H), 1.94 (m, 2H), 1.58 (m, 2H)

Example 105 Synthesis of{5-methyl-2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-oxazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)amine

{5-Methyl-2-[(S)-4-(2-morpholin-4-y l-ethyl)-4,5-dihydro-oxazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-y l)-amine

The compound obtained in Example 104 and morpholine were reactedaccording to the procedures as Preparation 33 and Example 15 in theorder to give the title compound.

¹H-NMR (400 HMz, CDCl₃); δ 10.11 (br s, 1H), 6.91 (s, 1H), 6.86 (s, 1H),6.34 (s, 1H), 4.60 (t, 1H), 4.48 (m, 1H), 4.10˜3.93 (m, 5H), 3.63˜3.52(m, 3H), 2.39 (, 3H), 2.07 (d, 2H), 1.94 (m, 2H), 1.58 (m, 2H)

Example 106˜125

The following exemplary compounds were prepared analogous to Preparation19, Step 3 of Preparation 35 and Preparation 36.

Example R2 R1 R4 ¹H NMR 106 H 1-ethylcarbamoyl- Cl (500 MHz, DMSO-d₆); δ11.03 (s, 1H), 7.76 (d, piperidin-4-yl J = 7.3 Hz, 2H), 7.44 (t, J = 7.3Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 6.76 (d, J = 1.85 Hz, 1H), 6.72 (d, J= 1.85 Hz, 1H), 6.47 (t, 1H), 6.25 (d, J = 1.85 Hz, 1H), 5.57 (m, 1H),3.90 (m, 2H), 3.58 (m, 1H), 3.02 (q, 2H), 2.87 (m, 2H) 1.96 (m, 2H),1.28 (m, 2H), 0.99 (t, 3H) 107 H 1-(tetrahydrofuran- H (500 MHz,DMSO-d₆); δ 11.94 (brs, 1H), 7.75 3-yl)carbonyl- (m, 2H), 7.44 (m, 2H),7.30 (m, 1H), 6.78 (s, pyrrolidin-3-yl 1H), 6.73 (s, 1H), 6.29 (s, 1H),5.59 (d, 1H), 4.30 (d, 1H), 3.96 (d, 1H), 3.86 (m, 1H), 3.72-3.60 (m,5H), 2.85 (m, 1H), 2.20 (m, 4H) 1.29 (m, 2H). 108 H tetrahydropyran-4-yl—CH₂—CO₂H (400 MHz, DMSO-d₆, Na salt); δ 10.88 (br s, 1H), 7.81 (d, J =8 Hz, 2H), 7.43 (m, 2H), 7.28 (m, 1H), 6.67 (s, 1H), 6.62 (s, 1H), 6.29(s, 1H), 5.23 (m, 1H), 3.92 (d, J = 8 Hz, 2H), 3.67 (m, 1H), 3.47 (m,2H), 3.14 (s, 2H), 2.06 (m, 2H), 1.48 (m, 2H) 109 H Cyclopentyl—CH₂—CO₂H (400 MHz, DMSO-d6, Na salt); δ 10.97 (br s, methyl 1H), 7.80(d, J = 8 Hz, 2H), 7.43 (t, 2H), 7.26 (t, 1H), 6.67 (s, 1H), 6.62 (s,1H), 6.20 (s, 1H), 5.33 (br s, 1H), 3.16 (s, 2H), 3.04 (m, 2H), 2.27 (m,1H), 1.86 (m, 2H), 1.60 (m, 4H), 1.33 (m, 2H) 110 H 1-methyl-piperidin-F (400 MHz, DMSO-d₆); δ 7.87 (d, 2H), 7.45 (t, 4-yl 2H), 7.31 (m, 1H),6.76 (s, 1H), 6.51 (s, 1H), 6.14 (s, 1H) 3.65 (br s, 1H), 3.41 (br s,2H), 2.99 (br s, 2H), 2.69 (s, 1H), 2.17 (br s, 2H), 1.79 (br s, 2H) 111H 1-hydroxy F (400 MHz, DMSO-d₆); δ 7.78 (d, 2H), 7.45 (t,ethyl-piperidin-4-yl 2H), 7.30 (t, 1H), 6.75 (s, 1H), 6.46 (d, 1H), 6.07(d, 1H), 3.37 (t, 2H), 3.36 (t, 1H), 2.90 (d, 2H), 2.45 (t, 2H), 2.20(t, 2H), 2.03 (t, 2H), 1.09 (t, 2H) 112 H 1-(tetrahydropyran- F (400MHz, CDCl₃); δ 7.78 (br s, 2H), 7.36 (br 4-yl)-piperidin-4-yl s, 2H),7.26 (br s, 1H), 6.71 (s, 1H), 6.68 (d, 1H), 6.12 (s, 1H), 3.90 (br s,2H), 3.46 (br s, 1H), 3.20 (br s, 2H), 3.09 (br s, 2H), 2.61 (br s, 1H),2.45 (br s, 2H), 2.23 (d, 2H), 1.87 (br sm 2H), 1.61 (br s, 2H), 1.58(br s, 2H) 113 H 1-(1,2-dioxo-thiano F (400 MHz, CDCl₃); δ 7.66 (d, 2H),7.44 (t, cyclohexyl-4-yl) 2H), 7.33 (t, 1H), 6.74 (d, 1H), 6.72 (d, 1H),piperidin-4-yl 6.26 (d, 1H), 3.39 (m, 1H), 3.22 (m, 2H), 2.92 (m, 4H),2.57 (t, 1H), 2.33 (m, 4H), 2.28 (m, 4H), 1.53 (m, 2H) 114 H TetrahydroOPh (400 MHz, CDCl₃); δ 8.12 (brs, 1H), 7.68 (m, pyran-4-yl 2H), 7.44(m, 2H), 7.34~ 7.25 (m, 3H), 7.01 (m, 3H), 6.74 (m, 2H), 6.35 (d, 1H),4.03 (m, 2H), 3.63-3.49 (m, 4H), 2.12 (m, 2H), 1.58 (m, 2H) 115 HMeO₂C—CH₂— F (400 MHz, CDCl₃); δ 7.56 (d, 2H), 7.41 (t, 2H), 7.34 (t,1H), 6.80 (d, 1H), 6.71 (s, 1H), 6.19 (d, 1H), 4.09 (s, 2H), 3.85 (s,3H) 116 H HO₂C—CH₂— F (400 MHz, DMSO-d₆); δ 7.91 (d, 2H), 7.41 (t, 2H),7.26 (t, 1H), 6.73 (s, 1H), 6.41 (d, 1H), 5.78 (d, 1H), 6.17 (br s, 1H),3.48 (s, 2H) 117 H MeO₂C—CH(Me)— Cl (400 MHz, CDCl₃); δ 8.62 (br s, 1H0,7.55 (d, J = 8 Hz, 2H), 7.38 (t, 2H), 7.30 (t, 1H), 7.00 (s, 1H), 6.60(s, 1H), 6.31 (s, 1H), 4.47 (br s, 1H), 4.27 (m, 1H), 1.58 (d, J − 8 Hz,3H) 118 H HO₂C—CH(Me)— Cl (400 MHz, DMSO-d₆, Na salt); δ 12.09 (br s,1H), 7.91 (d, J = 8 Hz, 2H), 7.42 (t, 2H), 7.27 (t, 1H), 6.72 (d, J = 8Hz, 1H), 6.21 (d, J = 8 Hz, 1H), 5.08 (s, 1H), 3.67 (t, 1H), 1.34 (d. J= 8 Hz, 3H) 119 H HO₂C—CH₂— OPh (500 MHz, MeOH-d4); δ 7.76 (d, J = 7.3Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.25 (m, 3H), 6.96 (t, J = 7.3 Hz,1H), 6.90 (d, J = 7.3 Hz, 2H), 6.68 (m, 1H), 6.53 (d, J = 1.85 Hz, 1H),6.00 (d, J = 1.35 Hz, 1H), 3.96 (s, 2H) 120 H HO₂C—CH(Me)— OPh (500 MHz,MeOH-d4); δ 7.76 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.25 (m,3H), 6.96 (t, J = 7.3 Hz, 1H), 5.90 (d, J = 7.3 Hz, 2H), 6.68 (m, 1H),6.53 (d, J = 1.85 Hz, 1H), 6.00 (d, J = 1.85 Hz, 1H), 3.96 (s, 2H) 121 H(tetrahydro pyran-4-yl) methyl

(400 MHz, DMSO-d₆); δ 11.79 (m, 1H), 7.91 (m, 2H), 7.51 (m, 2H), 7.39(m, 2H). 7.01 (m, 1H), 6.80 (m, 1H), 4.96 (m, 1H), 3.93 (m, 2H), 3.33(m, 3H), 3.15 (m, 2H), 2.87 (m, 2H), 2.75 (m, 1H), 1.95 (m, 1H), 1.79(m, 2H), 1.36 (m, 2H) 122 H cyclopentyl

(400 MHz, DMSO-d₆); δ 11.81 (s, 1H), 7.92 (m, 2H), 7.60 (m, 2H), 7.50(m, 2H), 7.34 (m, 1H), 6.83 (m, 1H), 4.99 (m, 1H), 3.95 (m, 1H), 3.70(m, 2H), 2.87 (m, 1H), 2.71 (m, 1H), 2.08 (m, 2H), 1.77 (m, 2H), 1.64(m, 4H) 123 4- Tetrahydro Cl (400 MHz, CDCl₃); δ 8.74 (br s, 1H), 7.53(d, MeO₂C—CH₂— pyran-4-yl J = 8 hz, 2H), 7.35 (d, J = 8 Hz, 2H), 7.05(s, 1H), 6.46 (s, 1H), 6.44 (s, 1H), 3.94 (d, 2H), 3.75 (m, 1H), 3.72(s, 3H), 3.67 (s, 2H), 3.61 (m, 2H), 2.13 (d, J + 8 Hz, 2H), 1.58 (m,2H) 124 4- (tetrahydro Cl (400 Mhz, CDCl₃); δ 8.40 (br s, 1H), 7.70 (d,MeO₂C—CH₂— pyran-4-yl)methyl J = 8 Hz, 2H), 7.32 (d, J = 8 Hz, 2H), 7.05(s, 1H), 6.67 (s, 1H), 6.43 (s, 1H), 3.95 (d, 2H), 3.73 (s, 3H), 3.67(S, 2h), 3.44 (T, 2h), 3.16 (D, j = 8 Hz, 2H), 1.98 (m, 1H), 1.79 (d, J= 12 Hz, 2H), 1.42 (m, 2H) 125 4- Tetrahydro Cl (400 Mhz, DMSO-d₆, Nasalt); δ 12.53 (s, 1H), HO₂C—CH₂— pyran-4-yl 7.70 (d, J = 8 Hz, 2H),7.30 (d, J = 8 Hz, 2H), 6.72 (s, 1H), 6.60 (s, 2H), 6.19 (s, 1H), 3.90(d, J = 12 Hz, 2H), 3.60 (m, 1H), 3.48 (m, 2H), 3.35 (s, 2H), 1.96 (d, J= 12 Hz, 2H), 1.59 (m, 2H)

Preparation 62: Synthesis of5-(1,1-dioxo-thiomorpolin-4-ylmethyl)-2-phenyl-1H-indol-7-yl amine

(Step 1)

7-Nitro-2-phenyl-1H-indole-5-carboxylic acid ethyl ester obtained inPreparation 59 was reacted according to the same procedures asPreparation 66 to give (7-nitro-2-phenyl-1H-indole-5-yl)-methanol.

(Step 2)

The compound obtained in Step 1, iodine and 1,1-dioxo-thiomorpholinewere reacted according to the same procedures as Preparation 37 andExample 15 in the order to give5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-7-nitro-2-phenyl-1H-indole.

(Step 3)

The compound obtained in Step 2 and iron dust were reacted according tothe same procedures as Step 3 of Preparation 35, to give the titlecompound.

Example 126 Synthesis of[5-(1,1-dioxo-thiomorpolin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-yl)-amine

[5-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-(tetrahydro-pyran-4-yl)-amine

The compound obtained in Preparation 62 and tetrahydropyran-4-one werereacted according to the same procedures as Preparation 36 to give thetitle compound.

¹H-NMR (500 MHz, CDCl₃); δ 8.38 (br s, 1H), 7.69 (d, J=7.3 Hz, 1H), 7.44(t, J=7.3 Hz, 2H), 7.32 (t, J=7.3 Hz, 1H), 7.00 (s, 1H), 6.75 (d, J=1.85Hz, 1H), 6.47 (d, J=1.85 Hz, 1H), 4.07 (m, 2H), 3.65 (m, 3H), 3.57 (m,2H), 3.02 (m, 8H), 2.12 (m, 2H), 1.61 (m, 2H)

Example 127˜138

The indole compound prepared by the method disclosed in Preparations 59,the commercially available amine compounds and carbonyl compounds werereacted according to the same procedures as Preparation 62 and Example126 in the order to give following exemplary compounds in the table.

Example R2 R1 R4' ¹H-NMR 127 H (tetrahydro 1,1-dioxo- (500 MHz, CDCl₃);δ 8.54 (br s, 1H), 7.67 pyran-4-yl) thiomorpholin- (d, J = 7.3 Hz, 1H),7.43 (t, J = 7.3 Hz, methyl 4-yl 2H), 7.32 (t, J = 7.3 Hz, 1H), 6.98 (s,1H), 6.75 (d, J = 1.85 Hz, 1H), 6.42 (d, J = 1.85 Hz, 1H), 4.07 (m, 2H),3.67 (s, 2H), 3.46 (m, 2H), 3.19 (m, 2H), 3.04 (m, 8H), 1.97 (m, 141),1.80 (m, 2H), 1.50 (m, 2H) 128 H (tetrahydro 1,1-dioxo- (400 MHz,DMSO-d₆); δ 7.78 (d, 2H), 7.45 pyran-4-yl) thiomorpholin- (t, 2H), 7.30(t, 1H), 6.75 (s, 1H), 6.46 methyl 4-yl (d, 1H), 6.07 (d, 1H), 3.37 (t,2H), 3.36 (t, 1H), 2.90 (d, 2H), 2.45 (t, 2H), 2.20 (t, 2H), 2.03 (t,2H), 1.09 (t, 2H) 129 H Tetrahydro 2-oxo- (400 MHz, DMSO-d₆); δ 11.04(s, 1H), 7.82 pyran-4-yl piperazin-4-yl (d, 2H), 7.50 (t, 2H), 7.34 (t,1H), 6.89 (s, 1H), 6.83 (s, 1H), 6.39 (s, 1H), 3.74 (m, 1H), 3.61 (br s,4H), 3.41 (m, 2H), 3.29 (br s, 4H), 3.18 (s, 2H), 3.12 (m, 2H), 2.24 (d,2H), 1.66 (m, 2H) 130 H 1-(tetra- 1,1-dioxo- (500 MHz, DMSO-d₆): δ 10.87(s, 1H), 7.75 hydrofuran-3- thiomorpholin- (d, 2H), 7.43 (t, 2H), 7.27(t, 1H), 6.72 yl)carbonyl 4-yl (s, 2H), 6.29 (s, 1H), 5.30 (d, 1H), 4.27piperidin-4-yl (d, 1H), 3.95 (d, 1H), 3.86 (m, 1H), 3.68 (m, 4H), 3.59(s, 2H), 3.37 (m, 1H), 3.27 (m, 1H), 3.06 (m, 4H), 2.92 (m, 1H), 2.84(m, 4H), 2.02 (m, 4H), 1.29 (m, 2H) 131 4-AcNH— Tetrahydro 1,1 -dioxo-(400 MHz, MzOH-d₄/CDCl₃); δ 9.28 (s, 1H), pyran-4-yl thiomorpholin- 7.55(d, J = 4 hz, 2H), 7.47 (d, J = 4 Hz, 2H), 4-yl 7.37 (s, 1H), 6.94 (s,1H), 6.63 (s, 1H), 6.42 (s, 1H), 4.10 (m, 2H), 3.58-3.69 (m, 5H), 3.02(m, 8H), 2.17 (s, 3H), 2.12 (m, 2H), 1.58 (m, 3H) 132 4-AcNH—Cyclopentyl 1,1-dioxo- (400 MHz, MeOH-d₄/CDCl₃; δ 9.08 (s, 1H),thiomorpholin- 7.48 (d, J = 8 Hz, 2H), 7.39 (dd, J1 = 8 Hz, 4-yl J2 = 4Hz, 2H), 6.89 (s, 1H), 6.60 (d, J = 4 Hz, 1H), 3.96 (m, 1H), 3.67 (s,2H), 3.00 (m, 8H), 2.18 (s, 3H), 2.06 (m, 2H), 1.26~ 1.77 (m, 6H) 1334-AcNH— (tetrahydro 1,1-dioxo- (400 MHz, MeOH-d₄/CDCl₃); δ 8.95 (s, 1H),pyran-4-yl) thiomorpholin- 7.57 (d, J = 4 Hz, 2H), 7.49 (d, J = 4 Hz,methyl 4-yl 2H), 7.33 (s, 1H), 7.00 (s, 1H), 6.65 (s, 1H), 6.40 (s, 1H),4.02 (m, 4H), 3.74 (s, 2H), 3.42 (t, 2H), 3.17 (d, J = 4 Hz, 2H), 3.02(m, 8H), 2.21 (s, 3H), 1.97 (m, 1H), 1.78 (m, 2H), 1.47 (m, 2H) 1344-MeO— Cyclopentyl 1,1-dioxo- (400 MHz, DMSO-d₆); δ 10.85 (s, 1H), 7.73thiomorpholin- (d, 2H), 7.05 (d, 2H), 6.71 (s, 1H), 6.61 4-yl (d, 1H),6.24 (s, 1H), 5.40 (d, 1H), 3.90 (m, 1H), 3.82 (s, 3H), 3.64 (s, 1H),3.10 (m, 4H), 2.89 (m, 4H), 2.05 (m, 2H), 1.77 (m, 2H), 1.64 (m, 2H),1.58 (m, 2H) 135 4-MeO— Tetrahydro 1,1-dioxo- (500 MHz, DMSO-d₆); δ10.79 (s, 1H), 7.67 pyran-4-yl thiomorpholin- (d, 2H), 7.01 (d, 2H),6.68 (s, 1H), 6.57 4-yl (s, 1H), 6.24 (s, 1H), 5.26 (d, 1H), 3.90 (m,2H), 3.77 (s, 3H), 3.61 (m, 1H), 3.58 (s, 2H), 3.46 (t, 2H), 3.33 (m,1H), 3.04 (m, 4H), 2.83 (m, 4H), 2.01 (d, 2H), 10.42 (m, 2H) 136 4-MeO—isopentyl 1,1-dioxo- (400 MHz, CDCl₃); δ 8.33 (s, 1H), 7.67thiomorpholin- (d, 2H), 7.43 (t, 2H), 7.31 (t, 1H), 6.98 4-yl (s, 1H),6.75 (s, 1H), 6.47 (s, 1H), 3.68 (s, 1H), 3.28 (t, 2H), 3.03 (m, 8H),2.63 (s, 1H), 1.82 (m, 1H), 1.65 (m, 2H), 1.00 (d, 6H) 137 3-F—Tetrahydro 1,1-dioxo- (400 MHz, CDCl₃); δ 8.31 (s, 1H), 7.46 pyran-4-ylthiomorpholin- (m, 3H), 7.07 (m, 2H), 6.82 (d, 1H), 6.55 4-yl (s, 1H),4.12 (m, 2H), 3.72 (m, 3H), 3.64 (t, 2H), 3.07 (m, 8H), 2.18 (d, 2H),1.66 (m, 2H) 138 3-F— Cyclopentyl 1,1-dioxo- (400 MHz, CDCl₃); δ 8.46(s, 1H), 7.50 thiomorpholin- (d, 1H), 7.42 (m, 2H), 7.06 (t, 1H), 7.024-yl (s, 1H), 6.80 (d, 1H), 6.51 (s, 1H), 1.03 (m, 1H), 3.72 (s, 2H),3.07 (m, 8H), 2.16 (m, 2H), 1.85 (m, 2H), 1.74 (m, 2H), 1.67 (m, 2H)

Preparation 63: Synthesis of3-bromo-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-7-nitro-2-phenyl-1H-indole

(Step 1)

5-Methyl-7-nitro-2-phenyl-1H-indole obtained during the process ofExample 46 and (BOC)₂O were reacted according to the same procedures asPreparation 23 to give 1-BOC-5-methyl-7-nitro-2-phenyl-indole.

(Step 2)

1-BOC-5-methyl-7-nitro-2-phenyl-indole (3.5 g, 10 mmol) obtained in Step1 was dissolved in carbon tetrachloride (30 mL), and theretoN-bromosuccinimide (NBS, 2.3 g, 13 mmol) and benzoyl peroxide (100 mg)were added. The mixture was refluxed under stirring for 4 hours at 80□.And then the mixture was filtered to remove solids, the filtrate wasdiluted with water and extracted with DCM. The solvent was removed underreduced pressure. The residue was purified by column chromatography togive 1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole (2.3 g, 46%).

(Step 3)

1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole (1.0 g, 2 mmol)obtained in Step 2 was dissolved in DCM (10 mL), and thereto Et₃N (560uL, 4 mmol) and 1,1-dioxo-thio-morpholine (300 mg, 3 mmol) were added.The mixture was stirred for 12 hours at room temperature. At the end ofthe reaction, added saturated aqueous NH₄Cl solution, extracted withDCM. After drying the extract, the solvent was removed under reducedpressure and the residue was purified by column chromatography to give1-BOC-3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indole(825 mg, 78%).

(Step 4)

1-BOC-3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indoleobtained in Step 3 (825 mg, 1.6 mmol) was dissolved in diethylether (5mL), and then HCl (4M dioxane solution, 5 mL). The reaction solution wasstirred for 2 hours at room temperature. At the end of the reaction,removed solvent under reduced pressure and dried to obtain3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indole,which was used in the next step without further purification.

Preparation 64: Synthesis of4-[(3-bromo-7-nitro-2-phenyl-1H-indol-5-yl)methyl]-morpholine

1-BOC-bromo-5-bromomethyl-7-nitro-phenyl-indole obtained in Step 2 ofPreparation 63 and morpholine were reacted to give the title compound,according to the same procedures as Step 3 and 4 of Preparation 63.

Example 139 Synthesis of3-bromo-5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-yl)-amine

[3-Bromo-5-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-(tetrahydro-pyran-4-yl)-amine

The compound obtained in Preparation 63 and tetrahydropyran-4-one werereacted according to the same procedures as Step 3 of Preparation 35 andPreparation 36 to give the title compound.

¹H-NMR (400 MHz, CDCl₃); δ 8.08 (br s, 1H), 7.61 (d, J=8 Hz, 2H), 7.44(t, 2H), 7.37 (s, 1H), 7.29 (m, 2H), 6.52 (s, 1H), 4.04 (dd, 2H), 3.44(t, 2H), 3.19 (d, J=4 Hz, 2H), 1.97 (m, 1H), 1.79 (d, J-12 Hz, 2H), 1.41(m, 2H)

Example 140 Synthesis of[3-bromo-(5-morpholin-4-yl)methyl-2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-yl)-amine

(3-Bromo-5-morpholin-4-ylmethyl-2-p henyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

The compound obtained in Preparation 64 and tetrahydropyran-4-one werereacted according to the same procedures as Step 3 of Preparation 35 andPreparation 36 to give the title compound.

¹H NMR (500 MHz, DMSO-d₆): δ 8.13 (brs, 1H), 7.81 (m, 2H), 7.49 (m, 2H),7.40 (m, 1H), 7.02 (s, 1H), 6.45 (s, 1H) 4.40 (m, 2H), 3.72 (m, 4H),3.67 (m, 1H), 3.6˜3.53 (m, 4H), 2.48 (m, 4H), 2.10 (m, 2H), 1.56 (m, 4H)

Example 141 Synthesis of [3-bromo-5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-cyclopentyl-amine

[3-Bromo-5-(1,1-dioxo-1 lambda*6*-thiomorpholin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-cyclopentyl-amine

The compound obtained in Preparation 63 and cyclopentanone were reactedaccording to the same procedures as Step 3 of Preparation 35 andPreparation 36 to give the title compound.

¹H-NMR (500 MHz, CDCl₃); δ 8.29 (br s, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.49(t, J=7.3 Hz, 2H), 7.39 (t, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.53 (d, J=1.85Hz, 1H), 3.95 (m, 1H), 3.70 (s, 2H), 3.02 (m, 8H), 2.10 (m, 2H), 1.77(m, 2H), 1.68 (m, 2H), 1.56 (m, 2H)

Example 142 Synthesis of[3-bromo-5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-2-phenyl-1H-indol-7-yl]-(tetrahydro-pyran-4-ylmethyl)-amine

[3-Bromo-5-(1,1-dioxo-1 lambda*6*-th iomorpholin-4-ylmethyl)-2-phenyl-1Hndol-7-yl]-(tetrahydro-pyran-4-yl methyl)-amine

The compound obtained in Preparation 63 andtetrahydropyran-4-carboxyaldehyde were reacted according to the sameprocedures as Step 3 of Preparation 35 and Preparation 36 to give thetitle compound.

¹H-NMR (500 MHz, CDCl₃); δ 8.20 (br s, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.49(t, J=7.3 Hz, 2H), 7.40 (t, J=7.3 Hz, 1H), 6.97 (s, 1H), 6.50 (d, J=1.85Hz, 1H), 4.03 (m, 2H), 3.71 (s, 2H), 3.42 (m, 2H), 3.18 (m, 2H), 3.03(m, 8H), 1.94 (m, 1H), 1.78 (m, 2H), 1.47 (m, 2H)

Preparation 65: Synthesis of 5-chloro-3-phenyl-7-nitro-1H-indole

(Step 1)

Commercially available 4-chloro-2-nitro-phenylamine (17.4 g, 131.5 mmol)was dissolved in ethanol (300 mL), and thereto silver nitrate (27 g,157.7 mmol) and iodine (40 g, 157.7 mmol) were added. The mixture wasstirred for 8 hours at room temperature. At the end of reaction, themixture was filtered using celite and washed with 100 ml of ethylacetateand concentrated. To the concentrate, added water and extracted withethylacetate. The organic layer was washed with saturated sodiumchloride solution and dried over anhydrous magnesium sulfate to give2-amino-5-chloro-3-nitro-phenyliodide (27.4 g, Yield 69%).

¹H-NMR (500 MHz, CDCl₃); δ 7.94 (s, 1H), 7.75 (s, 1H), 6.48 (br s, 2H),2.23 (s, 3H)

(Step 2)

2-Amino-5-chloro-3-nitro-phenyliodide (1.5 g, 4.90 mmol) obtained inStep 1 and 1-phenyl-2-trimethylsilylacetylene (4.3 g, 24.50 mmol) weredissolved in DMF (50 mL), and thereto palladium acetate (0.11 g, 0.5mmol), lithium chloride (0.21 g, 4.90 mmol) and triethylamine (2.48 g,24.50 mmol) were added. The mixture was heated under stirring for 3hours at 100° C. At the end of reaction, added water and extracted withethylacetate. The extract was washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed under reduced pressure and the residue was separatedby column chromatography to give5-chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.05 g, Yield87%).

¹H-NMR (400 HMz, CDCl₃); δ 9.78 (br s, 1H), 8.15 (s, 1H), 7.78 (s, 1H),7.38˜7.48 (m, 5H), 0.26 (s, 9H)

(Step 3)

5-Chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.5 g, 4.35 mmol)obtained in Step 2 was dissolved in tetrahydrofurane (30 mL), and 1 Mtetrabutylammoniumfluoride solution (5.2 mL, 5.2 mmol) was added indrops at 0° C. At the end of reaction, the resulting mixture was dilutedwith water and extracted with ethylacetate. The extract was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate and filtered. The solvent was removed under reduced pressure andthe residue was separated using column chromatography to give5-chloro-3-phenyl-7-nitro-1H-indole (1.2 g, Yield 100%).

¹H-NMR (400 HMz, CDCl₃); δ 10.03 (br s, 1H), 8.24 (d, J=8 Hz, 2H), 7.62(m, 3H), 7.55 (m, 2H), 7.43 (m, 1H)

Example 143 Synthesis of(5-chloro-3-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

(5-Chloro-3-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

5-Chloro-3-phenyl-7-nitro-1H-indole obtained in Preparation 65 andtetrahydropyran-4-one were reacted according to the same procedures asStep 3 of Preparation 35 and Preparation 36 to give the title compound.

¹H-NMR (400 MHz, CDCl₃); δ 8.10 (br s, 1H), 7.61 (d, J=8 Hz, 2H), 7.43(t, 2H), 7.38 (s, 1H), 7.31 (m, 2H), 6.56 (s, 1H), 4.05 (m, 2H), 3.65(m, 1H), 3.62 (t, 2H), 2.15 (d, J=12 Hz, 2H), 1.62 (m, 5H)

Example 144 Synthesis of(5-chloro-3-phenyl-1H-indol-7-yl)-(cyclopentyl)-amine

(5-Chloro-3-phenyl-1H-indol-7-yl)-c yclopentyl-amine

5-Chloro-3-phenyl-7-nitro-1H-indole obtained in Preparation 65 andcyclopentanone were reacted according to the same procedures as Step 3of Preparation 35 and Preparation 36 to give the title compound.

¹H-NMR (400 MHz, CDCl₃); δ 8.06 (br s, 7.58 (d, J=8 Hz, 2H), 7.39 (t,2H), 7.33 (s, 1H), 7.26 (m, 1H), 7.17 (s, 1H), 6.51 (s, 1H), 3.91 (m,1H), 2.08 (m, 2H), 1.74 (m, 2H), 1.66 (m, 2H), 0.54 (m, 2H)

Example 145 Synthesis of(5-chloro-3-phenyl-1H-indol-7-yl)-(tetrahydropyran-4-ylmethyl)-amine

(5-Chloro-3-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl)-amine

5-Chloro-3-phenyl-7-nitro-1H-indole obtained in Preparation 65 andtetrahydropyran-4-carboxylaldehyde were reacted according to the sameprocedures as Step 3 of Preparation 35 and Preparation 36 to give thetitle compound.

¹H-NMR (400 MHz, CDCl₃); δ 8.08 (br s, 1H), 7.61 (d, J=8 Hz, 2H), 7.44(t, 2H), 7.37 (s, 1H), 7.29 (m, 2H), 6.52 (s, 1H), 4.04 (dd, 2H), 3.44(t, 2H), 3.19 (d, J=4 Hz, 2H), 1.97 (m, 1H), 1.79 (d, J=12 Hz, 2H), 1.41(m, 2H)

Example 146 Synthesis of[5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-3-phenyl-2-trimethylsilanyl-1H-indol-7-yl]-(tetrahydropyran-4-yl)-amine

[5-(1,1-Dioxo-1 lambda*6*-thiomorpho lin-4-ylmethyl)-3-phenyl-2-trimethylsilanyl-1H-indol-7-yl]-(tetrahydro-pyran-4-yl)-amine

(Step 1)

4-Amino-3-nitro-benzoic acid ethyl ester andtrimethyl-phenylethynyl-silane were reacted according to the sameprocedures as Preparation 19 to give7-nitro-3-phenyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid ethylester.

(Step 2)

The compound obtained in Step 1, tetrahydropyran-4-one and 1,1-dioxo-thiomorpholine were reacted according to Preparation 62 and 36in the order to give the title compound.

¹H-NMR (400 MHz, CDCl₃); δ 8.00 (br s, 1H), 7.43 (m, 4H), 7.36 (m, 1H),6.92 (s, 1H), 6.55 (s, 1H), 4.08 (d, J=12 Hz, 2H), 3.67 (m, 1H), 3.66(s, 2H), 3.60 (t, 2H), 3.01 (d, 8H), 2.13 (d, J=12 Hz, 2H), 1.64 (m,2H),

Preparation 66: Synthesis of5-chloro-7-nitro-3-(2-oxo-piperazin-4-yl)methyl-2-phenyl-1H-indole

(Step 1)

7-nitro-5-chloro-2-phenyl-1H-indole (1.0 g, 3.67 mmol) obtained in theprocess of Example 59 was dissolved in dichloromethane (20 mL), andthereto phosphoryloxychloride (0.84 g, 5.50 mmol) and DMF (0.80 g, 11.01mmol) were added in drops at 0° C. The mixture was stirred at roomtemperature for 6 hours. At the end of reaction, added saturated aqueoussodium hydrogen carbonate solution to quench the reaction, and extractedwith ethylacetate. The extract was washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed under reduced pressure and the residue was separatedby column chromatography to give5-chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, Yield 45%).

¹H-NMR (400 HMz, DMSO-d₆); δ 9.89 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H),7.81 (d, J=9.2 Hz, 2H), 7.53 (m, 3H)

(Step 2)

5-Chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, 1.66 mmol) obtainedin Step 1 was dissolved in dichloromethane (20 mL), and thereto aceticacid (0.10 g, 1.66 mmol), 2-oxopiperazine (0.3 g, 3.32 mmol) and sodiumtriacetoxy borohydride (0.71 g, 3.32 mmol) were added in drops. Themixture was stirred at room temperature for 4 hours. At the end ofreaction, the mixture was diluted with water, and extracted withdichloromethane. The extract was washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed under reduced pressure and the residue was separatedby column chromatography to give5-chloro-7-nitro-3-(2-oxo-piperazin-4-yl)methyl-2-phenyl-1H-indole (0.55g, Yield 86%).

¹H-NMR (400 HMz, DMSO-d₆); δ 9.89 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H),7.81 (d, J=9.2 Hz, 2H), 7.53 (m, 3H)

Example 147 Synthesis of4-(5-chloro-7-cyclopentylamino-2-phenyl-1H-indol-3-ylmethyl)-piperazin-2-one

4-(5-Chloro-7-cyclopentylamino-2-phenyl-1H-indol-3-ylmethyl)-piperazin-2-one

The compound obtained in Preparation 66 and cyclopentanone were reactedaccording to the same procedures as Step 3 of Preparation 35 andPreparation 36 to give the title compounds.

¹H-NMR (400 MHz, DMSO-d₆); δ 11.07 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.71(s, 1H), 7.53 (t, 2H), 7.40 (t, 1H), 6.94 (s, 1H), 6.20 (s, 1H), 5.70(d, J=8 Hz, 1H), 3.88 (m, 1H), 3.61 (s, 2H), 3.31 (s, 2H), 2.96 (, 2H),2.59 (m, 2H), 2.03 (m, 2H), 1.74 (m, 2H), 1.64 (m, 2H), 1.54 (m, 2H)

Example 148 Synthesis of4-[5-chloro-2-phenyl-7-(tetrahydropyran-4-ylamino)-1H-indol-3-ylmethyl]-piperazin-2-one

4-[5-Chloro-2-phenyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-3-ylmethyl]-piperazin-2-one

The compound obtained in Preparation 66 and tetrahydropyran-4-one werereacted according to the same procedures as Step 3 of Preparation 35 andPreparation 36 to give the title compounds.

¹H-NMR (400 MHz, DMSO-d₆); δ 11.09 (s, 1H), 7.83 (d, J=8 Hz, 2H), 7.70(s, 1H), 7.54 (t, 2H), 7.40 (t, 1H), 6.96 (s, 1H), 6.31 (s, 1H), 5.64(d, J=8 Hz, 1H), 3.90 (d, J=12 Hz, 2H), 3.62 (m, 1H), 3.61 (s, 3H), 3.50(m, 2H), 3.31 (s, 2H), 2.96 (s, 2H), 2.59 (s, 2H), 2.00 (d, J=12 Hz,2H), 1.46 (m, 2H)

Example 149 Synthesis of4-{5-chloro-2-phenyl-7-[(tetrahydropyran-4-ylmethyl)-amino]-1H-indol-3-ylmethyl}-piperazin-2-one

4-{5-Chloro-2-phenyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-3-ylmethyl}-piperazin-2-one

The compound obtained in Preparation 66 andtetrahydropyran-4-carboxyaldehyde were reacted according to the sameprocedures as Step 3 of Preparation 35 and Preparation 36 to give thetitle compounds.

¹H-NMR (400 MHz, DMSO-d₆); δ 11.12 (s, 1H), 7.83 (d, J=5 Hz, 2H), 7.71(s, 1H), 7.54 (t, 2H), 7.40 (t, 1H), 6.96 (s, 1H), 6.21 (s, 1H), 5.73(m, 1H), 3.91 (d, J=12 Hz, 2H), 3.89 (s, 2H), 3.36 (m, 2H), 3.31 (s,2H), 3.10 (m, 2H), 2.96 (s, 2H), 2.59 (m, 2H), 1.90 (m, 1H), 1.74 (d,J=12 Hz, 2H), 1.34 (m, 2H)

Preparation 67: Synthesis of3-(4-methoxy-phenyl-1-yl)-7-nitro-1H-indazole

(Step 1)

7-Nitroindazole (1.60 g, 9.80 mmol) was dissolved in DMF (100 mL), andthereto potassiumhydroxide (2.20 g, 39.20 mmol) and iodine (4.98 g,19.61 mmol) were added in drops. The mixture was stirred for 2 hours,and diluted with 10% sodium bisulfite solution. The resulting solid wascollected and dried to give 3-iodo-7-nitro-1H-indazole (2.50 g, Yield88%).

¹H-NMR (400 HMz, CDCl₃); δ 11.49 (br s, 1H), 8.45 (d, J=8 Hz, 1H), 7.94(d, J=5 Hz, 1H), 7.41 (t, 1H)

(Step 2)

3-Iodo-7-nitro-1H-indazole (2.50 g, 8.65 mmol) obtained in Step 1 wasdissolved in acetone (50 mL), and thereto potassium hydroxide (0.73 g,12.97 mmol) and 4-methoxybenzylchloride (1.63 g, 10.38 mmol) were addedin drops at 0° C. The mixture was stirred for 2 hours. At the end ofreaction, the mixture was diluted with water, and extracted withethylacetate. The extract was washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed under reduced pressure and the residue was separatedby column chromatography to give3-iodo-7-nitro-1-(4-methoxybenzyl)-1H-indazole (3.2 g, Yield 91%).

¹H-NMR (400 HMz, CDCl₃); δ 8.08 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H),7.28 (m, 1H), 6.97 (d, J=8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 5.83 (s, 2H),3.72 (s, 3H)

(Step 3)

3-Iodo-7-nitro-1-(4-methoxybenzyl)-1H-indazole (1.50 g, 3.67 mmol)obtained in Step 2 was dissolved in dimethoxyethane (20 mL), and theretosodium carbonate (1.17 g, 11.01 mmol), 4-methoxyphenylboronic acid (0.84g, 5.50 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.43 g,0.37 mmol) were added in drops. The mixture was refluxed under stirringfor 2 hours. After cooling the solution, the reaction mixture wasdiluted with water, and extracted with ethylacetate. The extract waswashed with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate and filtered. The solvent was removed under reducedpressure and the residue was dissolved in trifluoroacetic acid (20 mL)and the resulting solution was refluxed under stirring for 5 hours andthen the solvent was removed under reduced pressure. The resultingresidue was diluted with water and extracted with ethylacetate. Theextract was washed with saturated sodium chloride solution, dried overanhydrous magnesium sulfate and filtered. The solvent was removed underreduced pressure and the residue was separated by column chromatographyto give 3-(4-methoxy-phenyl-1-yl)-7-nitro-1H-indazole (0.85 g, Yield86%).

¹H-NMR (400 HMz, CDCl₃); δ 11.33 (br s, 1H), 8.39 (t, 2H), 7.90 (d, J=8Hz, 2H), 7.36 (t, 1H), 7.08 (d, J=8 Hz, 2H), 3.91 (s, 3H)

Example 150 Synthesis ofcyclopentyl-[3-(4-methoxyphenyl)-1H-indazol-7-yl]-amine

Cyclopentyl-[3-(4-methoxy-phenyl)-1 H-indazol-7-yl]amine

The compound obtained in Preparation 67 and cyclopentanone were reactedaccording to the same procedures as Step 3 of Preparation 35 andPreparation 36 to give the title compounds.

¹H-NMR (400 MHz, CDCl₃); δ 7.83 (d, J=12 Hz, 2H), 7.31 (d, J=8 Hz, 1H),7.10 (t, 1H), 7.00 (dd, 2H), 6.53 (d, J=8 Hz, 1H), 3.91 (m, 1H), 3.86(s, 1H), 2.03 (m, 2H), 1.69 (m, 2H), 1.59 (m, 2H), 1.25 (m, 2H)

Example 151 Synthesis of[3-(4-methoxyphenyl)-1H-indazol-7-yl]-(tetrahydropyran-4-yl)-amine

[3-(4-Methoxy-phenyl)-1H-indazol-7-yl]-(tetrahydro-pyran-4-yl)-amine

The compound obtained in Preparation 67 and tetrahydropyran-4-one werereacted according to the same procedures as Step 3 of Preparation 35 andPreparation 36 to give the title compounds.

¹H-NMR (400 MHz, CDCl₃); δ 7.78 (d, J=12 Hz, 2H), 7.24 (d, J=8 Hz, 1H),7.06 (t, 1H), 6.98 (d, J=8 Hz, 2H), 6.45 (d, J=8 Hz, 1H), 3.93 (m, 2H),3.86 (s, 1H), 3.46 (t, 2H), 3.44 (m, 1H), 1.92 (d, J=12 Hz, 2H), 1.39(m, 2H)

Example 152 Synthesis of[3-(4-methoxyphenyl)-1H-indazol-7-yl]-(tetrahydropyran-4-ylmethyl)-amine

[3-(4-Methoxy-phenyl)-1H-indazol-7-yl]-(tetrahydro-pyran-4-ylmethyl)-amine

The compound obtained in Preparation 67 andtetrahydropyran-4-carboxyaldehyde were reacted according to the sameprocedures as Step 3 of Preparation 35 and Preparation 36 to give thetitle compounds.

¹H-NMR (400 MHz, CDCl₃); δ 7.78 (d, J=8 Hz, 2H), 7.29 (d, J=8 Hz, 1H),7.07 (t, 1H), 6.97 (d, J=8 Hz, 2H), 6.45 (d, J=8 Hz, 1H), 3.89 (m, 2H),3.86 (s, 1H), 3.24 (t, 2H), 3.04 (d, J=8 Hz, 2H), 1.73 (m, 1H), 1.57 (d,J=12 Hz, 2H), 1.30 (m, 2H)

Experimental Examples

Hereinafter, the effects provided by the present invention will beexplained through the following experimental examples. However, theeffects of the present invention are not limited to those exemplified bythe following experimental examples.

Experimental Example 1 Hepatocyte-Protecting Effect

If cells are isolated from in vivo environment and their culture orpreservation in vitro is begun, it would act as a stress to cells, andthe apoptosis mechanism would begin to work. For preservation of organsor tissues, it is necessary to protect them from such a primary stress.

In order to verify this, primary hepatocytes isolated from rats weretreated with the compounds of the working examples to observe how wellthe compounds can protect them from a primary stress. Primaryhepatocytes were isolated using the Seglen PO method (Experimental CellResearch 74 (1972) pp. 450-454). Briefly, hepatocytes were isolatedaccording to the two-step collagenase perfusion method and thencentrifuged using percoll gradient (Kreamer B L etc., In Vitro Cellular& Developmental Biology 22 (1986) pp. 201-211) at low speed (500 rpm)for 10 minutes to remove dead cells. Viability of hepatocytes wasmaintained at 90% or more. Cells were suspended in HepatoZYME media(Gibco BRL) and counted. 1.5×10⁴ cells of 100 μl were put into a 96-wellplate (BD biocoat) coated with collagen and attached to the bottom for3-4 hours. Then, as shown in FIG. 1, a caspase inhibitor, IDN6556 (LiverTransplantation (2003) 9: pp. 278-284), and the compound of Example 21were treated at a concentration of 1 or 10 μM. After 24, 72 or 144hours, cell viability was measured to evaluate a hepatocyte-protectingeffect.

Cell viability was measured by the optical density at 440 nm accordingto the WST-1 method (MK-400, Takeda). As shown in FIG. 1, viabilitydeclined rapidly in the control group which had been treated with onlyDMSO. In contrast, IDN6556 maintained viability after 72 hours up toabout 50%, compared with viability after 24 hours, and the compound ofExample 21 maintained viability after 144 hours up to 80% or more,compared with viability after 24 hours.

Experimental Example 2 Cell-Protecting Effect Against Cold Shock

In order to reproduce a condition for preservation prior to organtransplantation, primary cultured hepatocytes were prepared according toExperimental Example 1 and treated with the compounds of the workingexamples at 9 different concentrations that had been prepared by 3-foldserial dilution method using a starting concentration of 25 μM. Themixture was cultured at 37° C. for 1 hour, stored at 4° C. for 22 hours,and then transferred into an incubator at 37° C. and cultured therein.Cell viability was measured by the optical density at 440 nm accordingto the WST-1 method (MK-400, Takeda), and IC₅₀ (unit: μM) was obtainedusing prism software (see Table 1).

TABLE 1 Example (IC₅₀, μM) 5 <0.12 7 <0.4 16 3.56 17 <0.12 21 <0.12 220.97 24 <0.12 29 1.46 30 <0.12 32 <0.12 38 <0.12 40 <0.12 47 <0.12 510.26 56 0.20 58 <0.12 75 <0.12 76 <0.12 77 0.710 83 0.729 89 0.543 901.02 91 5.750 106 0.750 120 0.821 121 0.419 126 0.248 127 0.668 1322.874 133 0.571 134 0.437 135 0.39 136 0.585 137 0.158 138 0.216 1420.300 146 0.603

The same results as above were also obtained in other types of cellssuch as human embryonic lung cell line (LB-HEL) as well as hepatocytes(see FIG. 2 and Table 2). More specifically, LB-HEL cells were plated at1.5×10⁶ cells/well using DMEM medium (Gibco BRL) and treated with DMSO,nec-1, IM-54 or the compounds of Examples 126, 127, 137 and 138 atindicated concentrations. After storage at 4° C. for 24 hours, themixture was transferred into an incubator at 37° C. and culturedtherein. In order to verify recovery capacity at 37° C., cell viabilityafter 24 hours post-transfer was measured by the optical density at 440nm according to the WST-1 method (MK-400, Takeda) and compared with cellviability prior to cold shock (FIG. 2). The compounds of Examples 126,127, 137 and 138 exhibited a protecting effect against cold shock.However, neither nec-1, which inhibits necropoptosis (Nat Chem. Biol.(2005) 1:112-119), nor IDN6556, which inhibits apoptosis (pan-caspaseinhibitor), exhibited a significant protecting effect.

These results support the fact that the compounds of the presentinvention exhibit a remarkable effect in preventing and protectinginjury caused by cold shock and re-warming that necessarily occursduring organ transplantation or cell preservation.

TABLE 2 Example (IC₅₀, μM) 77 2.600 78 3.420 79 3.299 83 3.664 84 7.10891 0.664 92 2.123 93 0.530 94 0.200 95 <0.1 96 <0.1 97 <0.1 98 <0.1 990.097 100 0.532 101 0.345 109 <0.1 110 <0.1 111 <0.1 112 0.043 113 0.294114 0.580 116 1.180 118 0.400 119 0.418 120 4.145 121 0.462 122 0.240123 0.130 124 0.400 126 <0.1 127 0.042 128 0.056 134 0.664 135 0.344 1360.775 139 <0.1 140 <0.1 141 <0.1 142 <0.1 143 <0.1 144 <0.1 145 <0.1 1460.823 147 1.076 148 2.349 149 1.451 150 0.21 151 0.384 152 0.59 1380.473 137 0.071

Experimental Example 3 Protecting Effect Against Cold PreservationInjury in Rat-Isolated Perfusion Liver Model

In order to verify an organ preservation effect, rat-isolated perfusionliver model was used to evaluate a protecting effect of the compounds ofthe working examples against cold preservation injury. A white rat wasanesthetized by intraperitoneal injection of sodium pentobarbital (50mg/kg) and administered with heparin (500 U/kg) by intravenous injectionto prevent blood coagulation. After incising the abdominal median line,in order to measure bile output, polyethylene tube-10 was inserted intothe bile duct, and the coronary vein was tied. Polyethylene tube-190 wasinserted into the hepatic portal vein, and a perfusate, Krebs-Henseleitbicarbonate buffer (KHBB) (at pH 7.4 at 37° C.) was perfused at a rateof 4 mL/min/g. In order to prevent liver expansion caused by theperfusate, the inferior vena cava was opened, and then the liver wasisolated from the surrounding tissues. During the perfusion, a mixed gas(O₂ 95% and CO₂ 5%) was continuously injected to KHBB to supply oxygen.The isolated liver was perfused with KHBB for 5 minutes forstabilization, and then 10 mL of histidine-tryptophan-ketoglutarate(HTK) (at 4° C.) was flushed to remove KHBB. The control group and thetest groups were preserved at 4° C.: the former in 60 mL of HTK solutionand the latter in 60 mL of HTK solution to which the compound of Example126 at a concentration of 30 μM was added.

In order to observe a preservation effect of the test substancesdepending on the cold preservation period, the isolated liver waspreserved in cold storage condition (4° C.) for 6, 24, 48 and 72 hours,and 10 mL of HTK (4° C.) was flushed into the hepatic portal vein.Perfusate released at that moment was collected and measured for liverdamage markers, Lactate Dehydrogenase (LDH), Aspartate Aminotransferase(AST) and Alanine Aminotransferase (ALT) activity (FIG. 3). LDH, ALT andAST activity in the perfusate was measured according to the standardabsorption analysis method using a biochemical automatic analyzer,Hitachi 7150.

Experimental Example 4 Protecting Effect Against Cold Ischemia/WarmReperfusion Injury in Rat-Isolated Perfusion Liver Model

In order to verify a protecting effect against ischemia and reperfusioninjury that necessarily occurs during organ transplantation, therat-isolated perfusion liver model of Experimental Example 3 was used toevaluate the protecting effect of the compounds of the working examples.As in Experimental Example 3, the isolated liver was perfused with KHBBfor 5 minutes for stabilization, and then 10 mL ofhistidine-tryptophan-ketoglutarate (HTK) (at 4° C.) was flushed toremove KHBB. The control group and the treatment group were preserved at4° C.: the former in 60 mL of HTK solution and the latter in 60 mL ofHTK solution to which the compound of Example 126 at a concentration of30 μM was added. After 24 hours post-cold preservation, the isolatedliver was connected to a liver perfusion apparatus that maintains 37°C., and then KHBB (at pH 7.4 at 37° C.) was reperfused through thehepatic portal vein at a rate of 4 mL/min/g for 80 minutes. For the IPRLgroup without cold preservation, the isolated liver was not stored inHTK but immediately perfused with KHBB for 2 hours.

In order to observe a protecting effect against ischemia and reperfusioninjury, bile output and perfusate's LDH activity were measured. KHBBperfusate released from liver at 5, 10, 20, 30, 40, 50, 60, 70 and 80minutes after reperfusion was collected, and LDH activity in theperfusate was measured using a biochemical automatic analyzer, Hitachi7150 (FIG. 4). Bile secreted through the polyethylene tube which hadbeen inserted into the bile duct at 0˜20, 20˜40, 40˜60 and 60˜80 minutesafter reperfusion was collected, and bile output was measured (FIG. 5).

The results of measurement of activity of LDH that was released throughperfusate by reperfusion after 24-hour cold preservation of the isolatedliver are as follows. LDH activity in the perfusate of the IPRL groupwithout cold preservation was about 20˜110 U/L for 80 minutes ofreperfusion, which is the lowest LDH activity during reperfusion.However, LDH activity in the perfusate of the HTK group with coldpreservation in HTK solution for 24 hours was about 250˜680 U/L levelfor 80 minutes of reperfusion, which means that LDH activity wasoutstandingly increased, compared with the IPRL group during the time ofreperfusion. In contrast, the treatment group with 30 nM of a test drug,the compound of Example 126, inhibited LDH activity in the perfusate by50˜70% until 50 minutes of reperfusion, compared with the HTK group, andsignificantly inhibited liver cell damage caused by cold preservationand reperfusion (FIG. 4).

In the IPRL group without cold preservation, bile was secreted at a rateof 1.61˜2.40 μl/min/g at 0˜20, 20˜40, 40˜60 and 60˜80 minutes ofperfusion, and thus the total amount of bile output was 0.154±0.017 ml/gliver for 80 minutes of reperfusion. However, the total amount of bileoutput of the HTK group with cold preservation for 24 hours was0.044±0.006 ml/g liver, which means that bile output was substantiallydecreased by 70% or more, compared with the IPRL group. The total amountof bile output of the treatment group with 30 nM of the compound ofExample 126 was 0.070±0.006 ml/g liver, which means that the compoundsignificantly inhibited decline of bile output caused by coldpreservation and reperfusion (FIG. 5).

INDUSTRIAL APPLICABILITY

If the results herein are put together, it could be understood that thecompounds of the present invention can prevent necrocytosis of organscaused by reperfusion after cold storage and inhibit a decline of theirfunction. Thus, the compounds of the present invention are considered toexhibit a remarkable effect as a preservative in the organtransplantation process.

1. A composition for preserving cells and organs comprising as aneffective ingredient, a compound of the following formula (1) or apharmaceutically acceptable salt or isomer thereof:

wherein X represents C or N, n is 0 or 1, and n is 1 when X is C and nis 0 when X is N, A represents a direct bond, C₃-C₈-cycloalkyl, phenyl,or 5˜6-membered heteroaryl or heterocycle, each of which includes 1˜3heteroatoms selected from N, O and S atoms, R1 represents hydrogen,—C(O)—B—X′—R7 or —(CR5R6)_(m)-B—X′—R7, m is an integer of 0 to 4, eachof R5 and R6 independently represents hydrogen or C₁-C₅-alkyl, Brepresents a direct bond, C₃-C₈-cycloalkyl optionally containing oxo, or3˜10-membered heterocycle or heteroaryl, each of which includes 1˜3heteroatoms selected from O, S and N atoms, X′ represents a direct bond,—C(O)—, —SO₂—, —CO₂— or —C(O)NR5-, R7 represents hydrogen, C₁-C₆-alkyl,halogeno-C₁-C₆-alkyl, halogen, (CR5R6)_(m)-phenyl, (CR5R6)_(m)-hydroxyor (CR5R6)_(m)-heterocycle where the heterocycle optionally contains oxoand is a 3˜10-membered ring including 1˜3 heteroatoms selected from N, Oand S atoms, R2 represents —(CR5R6)_(m)-D-X″—R8, D represents a directbond or a 3˜10-membered heterocycle or heteroaryl, each of whichoptionally contains oxo and is optionally fused, and includes 1˜4heteroatoms selected from N, O and S atoms, X″ represents a direct bond,—C(O)—, —C(O)O—, —NR5C(O)—, —C(O)NR5- or —O—, R8 represents hydrogen,halogen, C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl, tri(C₁-C₆-alkyl)silane orhydroxy-C₁-C₆-alkyl, R3 represents hydrogen, halogen, cyano, nitro,aryl-R9 or (CR5R6)_(m)-D-R9, R9 represents hydrogen, halogen,C₁-C₆-alkyl, cyano, nitro or C₁-C₆-alkoxy, R4 represents—(CR5R6)_(m)—Y-D-R10, Y represents a direct bond, —C(O)O— or —O—, andR10 represents hydrogen, nitro, halogen, C₁-C₆-alkyl,carboxy-C₁-C₆-alkyl, aryl or —C(O)O—R5, wherein each of said alkyl,alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, halogen, nitrile, amino, C₁-C₆-alkylamino,di(C₁-C₆-alkyl)amino, C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl,C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkoxy and oxo.
 2. The compositionaccording to claim 1, wherein X represents C or N, n is 0 or 1, and n is1 when X is C and n is 0 when X is N, A represents a direct bond,phenyl, or 5˜6-membered heteroaryl or heterocycle, each of whichincludes 1˜3 heteroatoms selected from N, O and S atoms, R1 representshydrogen, —C(O)—B—X′—R7 or —(CR5R6)_(m)-B—X′—R7, m is an integer of 0 to2, each of R5 and R6 independently represents hydrogen or C₁-C₅-alkyl, Brepresents a direct bond, C₄-C₇-cycloalkyl optionally containing oxo, or4˜8-membered heterocycle or heteroaryl, each of which includes 1˜3heteroatoms selected from O, S and N atoms, X′ represents a direct bond,—C(O)—, —SO₂—, —CO₂— or —C(O)NH—, R7 represents hydrogen, C₁-C₆-alkyl,halogeno-C₁-C₆-alkyl, halogen, (CR5R6)_(m)-phenyl, (CR5R6)_(m)-hydroxyor (CR5R6)_(m)-heterocycle where the heterocycle optionally contains oxoand is a 4˜8-membered ring including 1˜3 heteroatoms selected from N, Oand S atoms, R2 represents —(CR5R6)_(m)-D-X″—R8, D represents a directbond or a 4˜8-membered heterocycle or heteroaryl, each of whichoptionally contains oxo and is optionally fused, and includes 1˜4heteroatoms selected from N, O and S atoms, X″ represents —C(O)—,—C(O)O—, —NR5C(O)—, —C(O)NR5- or —O—, R8 represents hydrogen, halogen,C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl, tri(C₁-C₆-alkyl)silane orhydroxy-C₁-C₆-alkyl, R3 represents hydrogen, halogen, cyano, nitro,aryl-R9 or (CR5R6)_(m)-D-R9, R9 represents hydrogen, halogen,C₁-C₆-alkyl, cyano, nitro or C₁-C₆-alkoxy, R4 represents—(CR5R6)_(m)—Y-D-R10, Y represents a direct bond, —C(O)O— or —O—, andR10 represents hydrogen, nitro, halogen, C₁-C₆-alkyl,carboxy-C₁-C₆-alkyl, aryl or —C(O)O—R5.
 3. The composition according toclaim 2, wherein the compound of the formula (1) has an indole structureof the following formula (1a) or an indazole structure of the followingformula (1b):


4. The composition according to claim 2, wherein A is selected from thegroup consisting of phenyl, pyridine, 1,4-pyrazine,4,5-dihydro-thiazole, thiazole, 4,5-dihydrooxazole, [1,2,4]oxadiazoleand [1,3,4]oxadiazole.
 5. The composition according to claim 2, whereinR1 represents —C(O)—B—X′—R7 or —(CHR5)_(m)—B—X′—R7 where m is an integerof 0 to 2; R5 represents C₁-C₃-alkyl; B represents a direct bond,C₅-C₆-cycloalkyl optionally containing oxo, or 5˜6-membered heterocycleor heteroaryl, each of which includes 1˜3 heteroatoms selected from O, Sand N atoms; X′ represents a direct bond, —C(O)—, —SO₂—, —CO₂— or—C(O)NH—; and R7 represents hydrogen, C₁-C₃-alkyl, halogeno-C₁-C₃-alkyl,halogen, (CH₂)_(m)-phenyl, (CH₂)_(m)-hydroxy or (CH₂)_(m)-heterocyclewhere the heterocycle optionally contains oxo and is a 5˜6-membered ringincluding 1˜3 heteroatoms selected from N, O and S atoms.
 6. Thecomposition according to claim 5, wherein B is selected from the groupconsisting of cyclopentyl, cyclohexyl, piperidine, tetrahydropyran,oxocyclohexyl, pyrrolidine, difluorocyclohexyl and tetrahydrofuran. 7.The composition according to claim 5, wherein R7 is selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, benzyl,hydroxymethyl, (morpholine-4-yl)-ethyl, tetrahydrofuran,2,2,2-trifluoroethyl, hydroxyethyl, 1,1-dioxothiomorpholine,tetrahydropyran, (tetrahydropyran-4-yl)-methyl and trifluoromethyl. 8.The composition according to claim 2, wherein D represents a directbond, or is selected from the group consisting of piperazine,pyrrolidine, morpholine, 1,1-dioxothiomorpholine and oxopiperazine. 9.The composition according to claim 2, wherein R8 is selected from thegroup consisting of hydrogen, ethyl, hydroxymethyl, methyl and fluorine.10. The composition according to claim 2, wherein R3 representshydrogen; halogen; phenyl optionally substituted with alkoxy; or6-membered heterocyclylmethyl including 1˜3 heteroatoms selected from N,S and O atoms as ring members and optionally containing oxo.
 11. Thecomposition according to claim 10, wherein R3 is selected from the groupconsisting of hydrogen, bromine, phenyl, methoxy-phenyl,morpholine-4-yl-methyl, oxopiperazine-4-yl-methyl and1,1-dioxo-thiomorpholine-4-yl-methyl.
 12. The composition according toclaim 2, wherein R4 represents —(CH₂)_(m)—Y-D-R10 where m is an integerof 0 to 2; Y represents a direct bond, —C(O)O— or —O—; D representspyridine or 5˜6-membered heterocycle including 1˜3 heteroatoms selectedfrom N, S and O atoms and optionally containing oxo; and R10 representshydrogen, halogen, C₁-C₃-alkyl, —(CH₂)—CO₂H, aryl or —C(O)O—R5.
 13. Thecomposition according to claim 12, wherein D is selected from the groupconsisting of 1,1-dioxo-thio-morpholine, oxopiperazine, pyridine,morpholine and 4,5-dihydro-thiazole.
 14. The composition according toclaim 12, wherein R10 is selected from the group consisting of hydrogen,fluorine, chlorine, bromine, methyl, ethyl and —(CH₂)—CO₂H.
 15. Thecomposition according to claim 2, wherein the compound is selected fromthe group consisting of:cyclopentyl-[2-(4,5-dihydro-1,3-thiazole-2-yl)-1H-indole-7-yl]-amine;[2-(4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-(4-methyl-cyclohexyl)-amine;[2-(4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-piperidine-4-yl-amine;2-5-[7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-[1,2,4]oxadiazole-3-yl}-ethanol;[(R)-2-(7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-1,3-thiazole-4-yl]-methanol;cyclopentyl-[2-((R)-4-pyrrolidine-1-ylmethyl-4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-amine;{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-methanol;[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-methanol;{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-methanol;{(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-methanol;[(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceticacid;[(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceticacid ethyl ester;2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-ethanol;1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-ethyl)-piperazine-1-yl]-2-hydroxy-ethanone;1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-thiazole-4-yl}-ethyl)-pyrrolidine-3-ol;[(R)-2-(5-bromo-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceticacid;[2-(7-cyclopentylamino-5-phenoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic acid;[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-acetic acid;3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-propionic acid ethyl ester;3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-4,5-dihydro-thiazole-4-yl]-propionic acid; cyclopentyl-(2-pyridine-2-yl-1H-indole-7-yl)-amine;cyclopentyl-(2-pyrazine-2-yl-1H-indole-7-yl)amine;(2-pyrazine-2-yl-1H-indole-7-yl)-(tetrahydropyran-4-yl)-amine;cyclopentyl-(2-thiazole-2-yl-1H-indole-7-yl)-amine;2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-4-carboxylicacid ethyl ester;2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-4-carboxylicacid;[2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-4-yl]-methanol;[2-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-thiazole-5-yl]-methanol;cyclopentyl-(5-methyl-2-[1,3,4]oxadiazole-2-yl-1H-indole-7-yl)-amine;cyclopentyl-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-(tetrahydro-pyran-4-yl)-amine;cyclohexyl-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;1-[4-(5-methyl-2-pyridine-2-yl-1H-indole-7-ylamino)-piperidine-1-yl]-ethanone;(1-methyl-piperidine-4-yl)-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;4-(5-methyl-2-pyridine-2-yl-1H-indole-7-ylamino)-cyclohexanone;(1-benzyl-pyrrolidine-3-yl)-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;cyclopentylmethyl-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-amine;N-(5-methyl-2-pyridine-2-yl-1H-indole-7-yl)-benzamide;cyclopentyl-(5-methyl-2-pyrazine-2-yl-1H-indole-7-yl)-amine;cyclopentyl-(5-ethoxy-2-pyridine-2-yl-1H-indole-7-yl)-amine;cyclopentyl-(5-phenoxy-2-pyridine-2-yl-1H-indole-7-yl)-amine;cyclopentyl-(3,5-dimethyl-2-phenyl-1H-indole-7-yl)-amine;cyclopentyl-(5-methyl-2-phenyl-1H-indole-7-yl)-amine;(2-cyclohexyl-5-methyl-1H-indole-7-yl)-cyclopentyl-amine;cyclopentyl-[5-methyl-2-(6-methyl-pyridine-2-yl)-1H-indole-7-yl]-amine;(5-methyl-2-phenyl-1H-indole-7-yl)-(tetrahydro-pyran-4-yl)-amine;(5-methyl-2-phenyl-1H-indole-7-yl)-(1-methyl-piperidine-4-yl)-amine;1-[4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-piperidine-1-yl]-ethanone;(5-methyl-2-phenyl-1H-indole-7-yl)-piperidine-4-yl-amine hydrochloride;2-hydroxy-1-[4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-piperidine-1-yl]-ethanone;(1-methanesulfonyl-piperidine-4-yl)-(5-methyl-2-phenyl-1H-indole-7-yl)-amine;4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-cyclohexanecarboxylic acid;4-(5-methyl-2-phenyl-1H-indole-7-ylamino)-cyclohexanecarboxylic acid(2-morpholine-4-yl-ethyl)-amide;cyclopentylmethyl-(5-methyl-2-phenyl-1H-indole-7-yl)-amine;(5-methyl-2-phenyl-1H-indole-7-yl)-(tetrahydro-pyran-4-ylmethyl)-amine;(5-chloro-2-phenyl-1H-indole-7-yl)-cyclopentyl-amine;(5-chloro-2-phenyl-1H-indole-7-yl)-(tetrahydro-pyran-4-yl)-amine;(5-chloro-2-phenyl-1H-indole-7-yl)-(1-methyl-piperidine-4-yl)-amine;(5-chloro-2-phenyl-1H-indole-7-yl)-cyclohexyl-amine;(1-benzyl-pyrrolidine-3-yl)-(5-chloro-2-phenyl-1H-indole-7-yl)-amine;4-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoic acid methylester; 4-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoic acid;[4-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-phenyl]-methanol;4-(7-cyclopentylamino-5-methyl-1H-indole-2-yl)-benzoic acid methylester; 2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoic acidmethyl ester; 2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-benzoicacid; [2-(5-chloro-7-cyclopentylamino-1H-indole-2-yl)-phenyl]-methanol;7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid ethylester;7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid;(7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-methanol;(7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-acetic acid ethyl ester;(7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-acetic acid;2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4S)-2-[5-chloro-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4S)-2-[7-[(4,4-difluorocyclohexyl)amino]-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]aceticacid;2-[(4S)-2-[7-(oxane-4-ylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4R)-2-[7-(oxane-4-ylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4R)-2-[7-(oxane-4-ylmethylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4S)-2-[7-(cyclopentylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]aceticacid;2-[(4S)-2-[7-[(1-acetylpyrrolidine-3-yl)amino]-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]aceticacid;2-[(4S)-2-[7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4S)-2-[7-(oxane-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]aceticacid;2-[(4S)-2-[7-(oxane-2-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4S)-2-[5-methyl-7-[[1-(3,3,3-trifluoropropanoyl)piperidine-4-yl]amino]-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]aceticacid;2-[(4R)-2-[7-(cyclopentylamino)-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4R)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;4-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]piperazine-2-one;2-[(4S)-4-[2-(1,1-dioxo-1,4-thiazinane-4-yl)ethyl]-4,5-dihydro-1,3-thiazole-2-yl]-5-methyl-N-(oxane-4-ylmethyl)-1H-indole-7-yl-amine;N-(4,4-difluorocyclohexyl)-5-methyl-2-[(4S)-4-(2-morpholine-4-ylethyl)-4,5-dihydro-1,3-thiazole-2-yl]-1H-indole-7-yl-amine;4-[2-[(4S)-2-[7-[(4,4-difluorocyclohexyl)amino]-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]piperazine-2-one;4-[2-[(4S)-2-[7-(oxane-4-ylmethylamino)-5-phenoxy-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]piperazine-2-one;2-[(4S)-4-(2-morpholine-4-ylethyl)-4,5-dihydro-1,3-thiazole-2-yl]-N-(oxane-4-ylmethyl)-5-phenoxy-1H-indole-7-amine;5-methyl-2-[(4S)-4-(2-morpholine-4-ylethyl)-4,5-dihydro-1,3-thiazole-2-yl]-N-(oxane-4-ylmethyl)-1H-indole-7-amine;1-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]piperidine-4-carboxyamide;[(2R)-1-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]pyrrolidine-2-yl]methanol;(2S)-1-[2-[(4S)-2-[5-methyl-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]pyrrolidine-2-carboxyamide;4-[2-[(4R)-2-[7-(cyclopentylamino)-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-thiazole-4-yl]ethyl]piperazine-2-one;2-[(4S)-2-[7-(cyclopentylamino)-5-methyl-1H-indole-2-yl]-4,5-dihydro-1,3-oxazole-4-yl]acetic acid;{(S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-oxazole-4-yl}-aceticacid;2-[(4S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indole-2-yl]-4,5-dihydro-1,3-oxazole-4-yl]ethanol;{5-methyl-2-[(S)-4-(2-morpholine-4-yl-ethyl)-4,5-dihydro-1,3-oxazole-2-yl]-1H-indole-7-yl}-(tetrahydro-pyran-4-yl)amine4-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]-N-ethylpiperidine-1-carboxyamide;[4-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]piperidine-1-yl]-(oxolan-3-yl)methanone;2-[7-(oxane-4-ylamino)-2-phenyl-1H-indole-5-yl]acetic acid;2-[7-(cyclopentylmethylamino)-2-phenyl-1H-indole-5-yl]acetic acid;5-fluoro-N-(1-methylpiperidine-4-yl)-2-phenyl-1H-indole-7-amine;2-[4-[(5-fluoro-2-phenyl-1H-indole-7-yl)amino]piperidine-1-yl]ethanone;5-fluoro-N-[1-(oxane-4-yl)piperidine-4-yl]-2-phenyl-1H-indole-7-amine;N-[1-(1,1-dioxan-4-yl)piperidine-4-yl]-5-fluoro-2-phenyl-1H-indole-7-amine;N-(oxane-4-yl)-5-phenoxy-2-phenyl-1H-indole-7-amine; methyl2-[(5-fluoro-2-phenyl-1H-indole-7-yl)amino]acetate;2-[(5-fluoro-2-phenyl-1H-indole-7-yl)amino]acetic acid; methyl2-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]propanoate;2-[(5-chloro-2-phenyl-1H-indole-7-yl)amino]propanoic acid;2-[(5-phenoxy-2-phenyl-1H-indole-7-yl)amino]acetic acid;2-[(5-phenoxy-2-phenyl-1H-indole-7-yl)amino]propanoic acid;2-[(4S)-2-[7-(oxane-4-ylmethylamino)-2-phenyl-1H-indole-5-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid;2-[(4S)-2-[7-(cyclopentylamino)-2-phenyl-1H-indole-5-yl]-4,5-dihydro-1,3-thiazole-4-yl]acetic acid; methyl2-[4-[5-chloro-7-(oxane-4-ylamino)-1H-indole-2-yl]phenyl]acetate; methyl2-[4-[5-chloro-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]phenyl]acetate;2-[4-[5-chloro-7-(oxane-4-ylamino)-1H-indole-2-yl]phenyl]acetic acid;5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-ylmethyl)-2-phenyl-1H-indole-7-amine;4-[[7-(oxane-4-ylamino)-2-phenyl-1H-indole-5-yl]methyl]piperazine-2-one;5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-phenyl-N-piperidine-4-yl-1H-indole-7-amine;[4-[[5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-phenyl-1H-indole-7-yl]amino]piperidine-1-yl]-(oxolan-3-yl)methanone;N-[4-[5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-7-(oxane-4-ylamino)-1H-indole-2-yl]phenyl]acetamide;N-[4-[7-(dicyclopentylamino)-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-1H-indole-2-yl]phenyl]acetamide;N-[4-[5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-7-(oxane-4-ylmethylamino)-1H-indole-2-yl]phenyl]acetamide;N-cyclopentyl-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(4-methoxyphenyl)-1H-indole-7-amine;5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(4-methoxyphenyl)-N-(oxane-4-yl)-1H-indole-7-amine;5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(3-methoxybutyl)-2-phenyl-1H-indole-7-amine;5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(3-fluorophenyl)-N-(oxane-4-yl)-1H-indole-7-amine;N-cyclopentyl-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-(3-fluorophenyl)-1H-indole-7-amine;3-bromo-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;3-bromo-5-(morpholine-4-ylmethyl)-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;3-bromo-N-cyclopentyl-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-2-phenyl-1H-indole-7-amine;3-bromo-5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-2-phenyl-1H-indole-7-amine;5-chloro-N-(oxane-4-yl)-3-phenyl-1H-indole-7-amine;5-chloro-N-cyclopentyl-3-phenyl-1H-indole-7-amine;5-chloro-N-(oxane-4-ylmethyl)-3-phenyl-1H-indole-7-amine;5-[(1,1-dioxo-1,4-thiazinane-4-yl)methyl]-N-(oxane-4-yl)-3-phenyl-2-trimethylsilyl-1H-indole-7-amine;4-[[5-chloro-7-(cyclopentylamino)-2-phenyl-1H-indole-3-yl]methyl]piperazine-2-one;4-[[5-chloro-7-(oxane-4-ylamino)-2-phenyl-1H-indole-3-yl]methyl]piperazine-2-one;4-[[5-chloro-7-(oxane-4-ylmethylamino)-2-phenyl-1H-indole-3-yl]methyl]piperazine-2-one; N-cyclopentyl-3-(4-methoxyphenyl)-1H-indazol-7-amine;3-(4-methoxyphenyl)-N-(oxane-4-yl)-1H-indazol-7-amine;3-(4-methoxyphenyl)-N-(oxane-4-ylmethyl)-1H-indazol-7-amine; and2-(7-cyclopentylamino-2-phenyl-1H-indole-5-yl)-ethanol.
 16. Thecomposition according to claim 1 for preserving cells, tissues andorgans, which comprises as an effective ingredient, a pharmaceuticallyacceptable salt or isomer of the compound of formula (1).
 17. Thecomposition according to claim 1, wherein the cell is animal cellisolated from tissues or organs of human or non-human animals andselected from the group consisting of liver cell, skin cell, mucousmembrane cell, Langerhans islet cell, nerve cell, cartilage cell,endothelium cell, epithelial cell, bone cell and muscle cell; or sperm,egg or fertilized egg of livestock or fish.
 18. The compositionaccording to claim 1, wherein the organ is selected from the groupconsisting of skin, cornea, kidney, heart, liver, pancreas, intestine,nerve, lung, placenta, umbilical cord and blood vessel.
 19. Thecomposition according to claim 1, wherein the tissue is selected fromthe group consisting of skin, cornea, kidney, heart, liver, pancreas,intestine, nerve, lung, placenta, umbilical cord and blood vessel. 20.The composition according to claim 1 for preventing injury of organs,isolated cell systems or tissues caused by cold storage, transplantoperation or post-transplantation reperfusion.
 21. A method of using thecomposition according to claim 1 for preserving cells, tissues or organsof animals for transplantation.
 22. A preparation method of acomposition for preserving cells, tissues or organs of animals,comprising a step of mixing a compound of formula (1) according to claim1 or a pharmaceutically acceptable salt or isomer thereof as aneffective ingredient, together with a pharmaceutically acceptablecarrier.
 23. A method of using the composition according to claim 20 forcultivating or preserving cells, tissues or organs, in manufacturing anartificial organ.